JP5908410B2 - Bicyclic derivatives useful as inhibitors of DPP-1 - Google Patents

Description

  The present invention is directed to novel bicyclic derivatives, pharmaceutical compositions containing them, and their use in the treatment of disorders and conditions modulated by DPP-1.

  Chronic obstructive pulmonary disease (COPD) is characterized by a progressive development of irreversible airflow limitation. COPD consists of chronic obstructive bronchitis with obstruction of the peripheral airway and emphysema with enlargement of the void and destruction of the lung parenchyma, loss of lung elasticity, and closure of the peripheral airway. Patients with COPD had an increase in neutrophil count, cytotoxic T lymphocyte count, and macrophage count in bronchoalveolar lavage (BAL) of the airways and lung parenchyma. The presence of these inflammatory cells correlates with the severity of airway obstruction and alveolar wall destruction. It has been found that neutrophil elastase, cathepsin G and proteinase 3, can lead to emphysema and mucus hypersecretion in laboratory animals. Granzymes A and B are neutral serine proteases that are expressed only in activated cytotoxic T lymphocyte granules. In COPD, the protease-antiprotease balance appears to favor increased proteolysis due to the increase in polymorphonuclear neutrophil (PMN) derived proteases, cathepsins, and matrix metalloproteinases (MMPs). Thus, drugs that inhibit all or most of the related proteases described above are expected to be effective in treating COPD.

  Dipeptidyl peptidase-1 (DPP-1, cathepsin C) is a member of the lysosomal papain cysteine protease family that also includes cathepsins B, K, H, L, O, and S. DPP-1 (molecular weight 200 kd) is composed of dimers of disulfide-bonded heavy and light chains, all from a single protein precursor. DPP-1 mRNA is highly expressed in tissues such as lung, spleen, kidney, and liver, and similarly in inflammatory cells such as PMN, cytotoxic T lymphocytes, alveolar macrophages, and mast cells. The biological function of DPP-1 is to convert an inactive proenzyme to an active enzyme by removing a dipeptide from the N-terminus. Proenzymes activated by DPP-1 are PMN-derived proteases, granzymes A and B, chymase, and tryptase. Since these enzymes play an important pathological role in COPD, inhibition of DDP-1 by small molecules would be a reasonable therapeutic intervention for COPD. Further therapeutic indications for DPP-1 inhibitors are asthma, rhinitis, and rheumatoid arthritis.

  For the treatment of DPP-1-mediated disorders and medical conditions, including but not limited to rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, sepsis, irritable bowel disease, cystic fibrosis, and abdominal aortic aneurysm There remains a need for inhibitors of DPP-1.

  The present invention relates to formula (I):

[Where:
R ¹ is selected from the group consisting of C _1-4 alkyl, —C (O) —NH ₂ , C _3-6 cycloalkyl, phenyl, and 5-6 membered heteroaryl, where heteroaryl is halogen and C ₁ Optionally substituted with one or more substituents independently selected from the group consisting of _˜4 alkyls,
n is an integer of 0 to 1,
L is

Selected from the group consisting of —CH ₂ CH ₂ —NR ^A —, and —CH ₂ CH ₂ CH ₂ —NR ^A —, wherein R ^A is selected from the group consisting of hydrogen, methyl, and ethyl; Here, the L substituent is incorporated into the compound of formula (I) as depicted, and more specifically, the L substituent is an N atom of the L substituent where C ( Incorporated in the compound of formula (I) to bind to O)),
Y is selected from the group consisting of N and CH;
X is selected from the group consisting of N (R ^B ), O, and S, wherein R ^B is selected from the group consisting of hydrogen and C _1-4 alkyl;
R ² is selected from the group consisting of hydrogen, halogen, nitro, —CO ₂ H, —C (O) —NR ^C R ^D , —Q, —O—Q, and —C (O) —NH—Q. ,
Where R ^C and R ^D are each independently selected from the group consisting of hydrogen and C _1-4 alkyl, or R ^C and R ^D together with the nitrogen atom to which they are attached. Piperidin-1-yl, piperazin-1-yl, pyrrolidin-1-yl, morpholin-4-yl, 1,2,3,4-tetrahydroquinolin-1-yl, and 1,2,3,4-tetrahydro -Forming a cyclic structure selected from the group consisting of isoquinolin-2-yl,
Q is selected from the group consisting of aryl, aralkyl, heterocyclyl, benzo [d] [1,3] dioxolyl, and 2,3-dihydro-benzo [b] [1,4] dioxinyl;
The aryl or heterocyclyl, whether alone or as part of a substituent, is halogen, cyano, C _1-4 alkyl, halogenated C _1-4 alkyl, C _1-4 alkoxy, halogenated C One or more substituents independently selected from the group consisting of _1-4 alkoxy, —CO ₂ H, —C (O) —NR ^E R ^F , —SO ₂ —NR ^E R ^F , and phenyl; Optionally substituted, wherein R ^E and R ^F are each independently selected from the group consisting of hydrogen and C _1-4 alkyl;
The heterocyclyl may contain one or more S heteroatoms, and the heterocyclyl may be optionally further substituted with 1-2 oxo groups on the one or more S heteroatoms. ]
And a pharmaceutically acceptable salt thereof.

  The present invention is a compound of formula (II) comprising:

R ¹ is selected from the group consisting of C _1-4 alkyl, —C (O) —NH ₂ , C _3-6 cycloalkyl, phenyl, and 5-6 membered heteroaryl, wherein the heteroaryl is Optionally substituted with one or more substituents independently selected from the group consisting of halogen and C _1-4 alkyl;
n is an integer of 0 to 1,
L is selected from the group consisting of —CH ₂ CH ₂ —NR ^A — and —CH ₂ CH ₂ CH ₂ —NR ^A —, where R ^A is selected from the group consisting of hydrogen, methyl, and ethyl. , (L substituents are incorporated into compounds of formula (I) as depicted, and more specifically, L substituents are those wherein the N atom of the L substituent is C (O Embedded in the compound of formula (I) to bind to
X is selected from the group consisting of N (R ^B ), O, and S, wherein R ^B is selected from the group consisting of hydrogen and C _1-4 alkyl;
R ² is selected from the group consisting of hydrogen, halogen, nitro, —CO ₂ H, —C (O) —NR ^C R ^D , —Q, —O—Q, and —C (O) —NH—Q. ,
Where R ^C and R ^D are each independently selected from the group consisting of hydrogen and C _1-4 alkyl, or R ^C and R ^D together with the nitrogen atom to which they are attached, Piperidin-1-yl, piperazin-1-yl, pyrrolidin-1-yl, morpholin-4-yl, 1,2,3,4-tetrahydroquinolin-1-yl, and 1,2,3,4-tetrahydro- Forming a cyclic structure selected from the group consisting of isoquinolin-2-yl,
Q is selected from the group consisting of aryl, aralkyl, heterocyclyl, benzo [d] [1,3] dioxolyl, and 2,3-dihydro-benzo [b] [1,4] dioxinyl;
The aryl or heterocyclyl, whether alone or as part of a substituent, is halogen, cyano, C _1-4 alkyl, halogenated C _1-4 alkyl, C _1-4 alkoxy, halogenated C _1. Optional with one or more substituents independently selected from the group consisting of _˜4 alkoxy, —CO ₂ H, —C (O) —NR ^E R ^F , —SO ₂ —NR ^E R ^F , and phenyl Wherein R ^E and R ^F are each independently selected from the group consisting of hydrogen and C _1-4 alkyl;
The heterocyclyl contains one or more S heteroatoms, and the heterocyclyl may be further optionally substituted with 1-2 oxo groups on the one or more S heteroatoms,
It is further aimed at said compounds, and pharmaceutically acceptable salts thereof.

  The present invention is further directed to a process for the preparation of compounds of formula (I) and / or compounds of formula (II). The present invention is further directed to products manufactured according to the processes described herein.

  Illustrative of the invention are pharmaceutical compositions comprising a pharmaceutically acceptable carrier and products manufactured according to the processes described herein. Illustrative of the invention is a pharmaceutical composition made by mixing a product made according to the process described herein and a pharmaceutically acceptable carrier. Illustrative of the invention is a method of making a pharmaceutical composition comprising mixing a product made according to the process described herein and a pharmaceutically acceptable carrier.

  Illustrating the invention are disorders mediated by DPP-1 (cathepsin C) (eg, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, sepsis, irritable bowel disease, cystic fibrosis, and abdominal aorta A method of treating in a patient in need of treatment of a disorder selected from the group consisting of aneurysms, comprising administering to the patient a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above Is the way.

  Another example of the present invention is (a) rheumatoid arthritis, (b) asthma, (c) chronic obstructive pulmonary disease, (d) sepsis, (e) irritable bowel disease, (f) cystic fibrosis, Or (g) in a patient in need of treatment for an abdominal aortic aneurysm, the use of any compound described herein for the preparation of a medicament for treating them.

  In another example, the present invention is for treating a disorder selected from the group consisting of rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, sepsis, irritable bowel disease, cystic fibrosis, and abdominal aortic aneurysm. A compound as described herein is intended for use in the method.

  The present invention relates to formula (I):

Wherein R ¹ , R ² , X, Y, L, and n are as defined herein. And a pharmaceutically acceptable salt thereof. The present invention further comprises formula (II):

Wherein R ¹ , R ² , X, Y, L, and n are as defined herein. And a pharmaceutically acceptable salt thereof. The compounds of formula (I) and formula (II) of the present invention include rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, sepsis, irritable bowel disease, cystic fibrosis, and abdominal aortic aneurysm. Inhibitors of DPP-1 useful in the treatment of disorders, diseases, and conditions mediated by, but not limited to, DPP-1 (cathepsin C).

^One skilled in the art will recognize that several variables (eg, R ¹ , R ² , X, L, and n, etc.) appear in compounds of formula (I) and compounds of formula (II). One skilled in the art will recognize that when a particular substituent is selected for a given variable for a compound of formula (I), the selection is not intended to limit the scope of the variable for a compound of formula (II) Will be further recognized. Similarly, the choice of a particular substituent for a given variable for a compound of formula (II) is not intended to limit the scope of said variable for a compound of formula (I).

In one embodiment of the invention, R ¹ is selected from the group consisting of C _1-4 alkyl, —C (O) —NH ₂ , C _3-6 cycloalkyl, and 5-6 membered heteroaryl, wherein The 5- to 6-membered heteroaryl is optionally substituted with 1-2 substituents selected from the group consisting of halogen and C _1-4 alkyl. In another embodiment of the invention, R ¹ is selected from the group consisting of C _1-4 alkyl, —C (O) —NH ₂ , C _4-6 cycloalkyl, and 5-6 membered heteroaryl, wherein Wherein the 5-6 membered heteroaryl is optionally substituted with one substituent selected from the group consisting of halogen and C _1-4 alkyl.

In another embodiment of the invention, R ¹ is ethyl, cyclobutyl, thien-2-yl, thien-3-yl, 2-bromo-thien-2-yl, 5-chloro-thien-2-yl, thiazole Selected from the group consisting of 2-yl, 4-methyl-thiazol-2-yl, pyrazol-1-yl, flur-2-yl, 1-methyl-imidazol-4-yl, and amino-carbonyl. In another embodiment of the invention, R ¹ is selected from the group consisting of ethyl, thien-2-yl, thiazol-2-yl, fur-2-yl, and 1-methyl-imidazol-4-yl. . In another embodiment of the present invention, R ¹ is selected from the group consisting of ethyl, thien-2-yl, thiazol-2-yl, and fur-2-yl. In another embodiment of the present invention, R ¹ is selected from the group consisting of ethyl, thien-2-yl, and thiazol-2-yl. In another embodiment of the present invention, R ¹ is thien-2-yl.

In another embodiment of the present invention, R ¹ is C _{1 to 4} alkyl. In another embodiment of the present invention, R ¹ is C _{1 to 2} alkyl. In another embodiment of the present invention, R ¹ is ethyl.

  In one embodiment of the present invention, n is 0. In another embodiment of this invention n is 1.

  In one embodiment of the invention, L is

It is. In another embodiment of the invention, L is selected from the group consisting of —CH ₂ CH ₂ —N (R ^A ) — and —CH ₂ CH ₂ CH ₂ —N (R ^A ) —, wherein R ^A is selected from the group consisting of hydrogen, methyl, and ethyl. In another embodiment of this invention L is —CH ₂ CH ₂ CH ₂ —N (R ^A ) —, wherein R ^A is selected from the group consisting of hydrogen, methyl, and ethyl. In another embodiment of this invention L is —CH ₂ CH ₂ —NR ^A —. In another embodiment of this invention L is —CH ₂ CH ₂ CH ₂ —NR ^A —. In another embodiment of this invention L is —CH ₂ CH ₂ CH ₂ —NH—.

  In one embodiment of the invention, L is

Selected from the group consisting of —CH ₂ CH ₂ —N (R ^A ) —, and —CH ₂ CH ₂ CH ₂ —N (R ^A ) —, where R ^A consists of hydrogen, methyl, and ethyl. Selected from the group. In another embodiment of the invention L is

—CH ₂ CH ₂ —NH—, —CH ₂ CH ₂ CH ₂ —NH—, —CH ₂ CH ₂ CH ₂ —N (CH ₃ ) —, and —CH ₂ CH ₂ CH ₂ —N (CH ₂ CH ₃ )-. In another embodiment of the invention L is

_{-CH 2 CH 2 -NH -, -} CH 2 CH 2 CH 2 -NH-, and _{-CH 2 CH 2 CH 2 -N (} CH 2 CH 3) - is selected from the group consisting of. In another embodiment of the invention L is

It is selected from the group consisting of —CH ₂ CH ₂ CH ₂ —NH— and —CH ₂ CH ₂ CH ₂ —N (CH ₂ CH ₃ ) —. In another embodiment of the invention L is

And —CH ₂ CH ₂ CH ₂ —NH—.

In one embodiment of the present invention, R ^A is selected from the group consisting of hydrogen, methyl, and ethyl. In another embodiment of the present invention, R ^A is hydrogen.

  In one embodiment of the invention,

Is selected from the group consisting of indolyl, 1-methyl-indolyl, benzofuryl, benzothienyl, and benzimidazolyl.

In one embodiment of the present invention, Y is selected from the group consisting of N and CH, and X is selected from the group consisting of N (R ^B ), O, and S, provided that X is O or S In some cases, Y is CH.

In one embodiment of the present invention, Y is N. In another embodiment of the invention, Y is CH. In one embodiment of the present invention, X is O. In another embodiment of the invention X is S. In another embodiment of the invention, X is NR ^B. In another embodiment of the invention, R ^B is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, and t-butyl. In another embodiment of the present invention, R ^B is selected from hydrogen, methyl, and from the group consisting of ethyl. In another embodiment of the present invention, R ^B is selected from the group consisting of hydrogen and methyl. In another embodiment of the present invention, R ^B is hydrogen.

In one embodiment of the invention, Y is selected from the group consisting of N and CH, and X is selected from the group consisting of N (R ^B ), O, and S, where R ^B is hydrogen and Selected from the group consisting of C _1-2 alkyl. In another embodiment of the invention, Y is selected from the group consisting of CH and N, and X is selected from the group consisting of NH, N (CH ₃ ), and O, provided that when X is O. , Y is CH. In another embodiment of the invention, Y is selected from the group consisting of CH and N, and X is selected from the group consisting of NH and O, provided that when X is O, Y is CH. In another embodiment of the invention, Y is CH and X is NH.

  In one embodiment of the invention,

Is selected from the group consisting of indolyl and benzothienyl. In another embodiment of the present invention, X is selected from the group consisting of N (R ^B) and S, wherein R ^B is selected from the group consisting of hydrogen and C _{1 to 2} alkyl. In another embodiment of the invention, X is selected from the group consisting of S and NH.

In one embodiment of the invention, R ² is hydrogen, halogen, nitro, —CO ₂ H, —C (O) —NR ^C R ^D , phenyl, —O-phenyl, heterocyclyl, and —C (O) —. Selected from the group consisting of NH-Q, wherein R ^C and R ^D are each independently selected from the group consisting of hydrogen and C _1-4 alkyl, or R ^C and R ^D are Together with the nitrogen atom to which is bonded, piperidin-1-yl, pyrrolidin-1-yl, 1,2,3,4-tetrahydroquinolin-1-yl, and 1,2,3,4-tetrahydro-isoquinoline Forming a cyclic structure selected from the group consisting of 2-yl;
Q is selected from the group consisting of aryl, aralkyl, heterocyclyl, benzo [d] [1,3] dioxolyl, and 2,3-dihydro-benzo [b] [1,4] dioxinyl, wherein the aryl or heterocyclyl is alone or regardless in either as part of a substituent group, a halogen, cyano, C _{1 to 4} alkyl, fluorinated C _{1 to 4} alkyl, C _{1 to 4} alkoxy, fluorinated C _{1 to 4} alkoxy, - Optionally substituted with one to two substituents independently selected from the group consisting of CO ₂ H, —C (O) NR ^E R ^F , —SO ₂ —NR ^E R ^F , and phenyl, wherein R ^E and R ^F are each independently selected from the group consisting of hydrogen and C _1-2 alkyl, the heterocyclyl containing one or more S heteroatoms, wherein the heterocyclyl is the one or more S heteroatoms. Up In the above, it may be further optionally substituted with 1 to 2 oxo groups.

In another embodiment of the invention, R ² is from hydrogen, halogen, nitro, carboxy, phenyl, —O-phenyl, —C (O) —NR ^C R ^D , and —C (O) —NH—Q. Wherein R ^C and R ^D are each independently selected from the group consisting of hydrogen and C _1-2 alkyl, or R ^C and R ^D are the nitrogen to which they are attached. Taken together with the atoms to form a cyclic structure selected from the group consisting of 1,2,3,4-tetrahydroquinolin-1-yl and 1,2,3,4-tetrahydro-isoquinolin-2-yl;
Q is from the group consisting of phenyl, naphthyl, —C _1-2 alkyl-phenyl, heterocyclyl, benzo [d] [1,3] dioxolyl, and 2,3-dihydro-benzo [b] [1,4] dioxinyl. And the phenyl or heterocyclyl, whether alone or as part of a substituent, is halogen, cyano, C _1-4 alkyl, fluorinated C _1-2 alkyl, C _1-4 alkoxy, Optionally with 1 to 2 substituents independently selected from the group consisting of fluorinated C _1-2 alkoxy, —CO ₂ H, —C (O) NH ₂ , —SO ₂ —NH ₂ , and phenyl. Substituted, the heterocyclyl contains one or more S heteroatoms, and the heterocyclyl may be optionally substituted with 1-2 oxo groups on the one or more S heteroatoms.

In another embodiment of the present invention, R ² is hydrogen, 5-bromo, 5- (carboxy) 5- (nitro), 5- (phenyl), 5- (4-fluorophenyl) 5- (4 -Methoxy-phenyl), 5- (3,4-dimethoxy-phenyl), 5- (3,5-dimethoxy-phenyl), 5- (3-cyano-phenyl), 5- (3-carboxy-phenyl), 5- (4-carboxy-phenyl), 5- (4-trifluoromethyl-phenyl), 5- (4-trifluoromethoxy-phenyl), 5- (3,5-di (trifluoromethyl) -phenyl) , 5- (2- (aminocarbonyl) -phenyl), 5- (3- (aminocarbonyl) -phenyl), 5- (4- (aminocarbonyl) -phenyl), 5- (3- (aminosulfonyl)- Phenyl), 5- ( Enoxy), 5- (3,4-dimethoxy-phenoxy), 6- (diethylamino-carbonyl), 5- (phenyl-amino-carbonyl), 5- (3-chlorophenyl-amino-carbonyl), 5- (4- Chlorophenyl-amino-carbonyl), 5- (2-fluorophenyl-amino-carbonyl), 5- (3-fluorophenyl-amino-carbonyl), 5- (4-fluorophenyl-amino-carbonyl), 5- (3 -Methylphenyl-amino-carbonyl), 5- (4-methylphenyl-amino-carbonyl), 5- (2-isopropylphenyl-amino-carbonyl), 5- (4-isopropylphenyl-amino-carbonyl), 5- (4-t-butylphenyl-amino-carbonyl), 5- (2-methoxyphenyl-amino-carbonyl) Rubonyl), 5- (3-methoxyphenyl-amino-carbonyl), 5- (4-methoxyphenyl-amino-carbonyl), 5- (3,4-difluorophenyl-amino-carbonyl), 5- (3,4 -Dichlorophenyl-amino-carbonyl), 5- (3,4-dimethylphenyl-amino-carbonyl), 5- (2,6-dimethylphenyl-amino-carbonyl), 5- (3,4-dimethoxyphenyl-amino-) Carbonyl), 5- (3,5-dimethoxyphenyl-amino-carbonyl), 5- (naphth-1-yl-amino-carbonyl), 5- (benzyl-amino-carbonyl), 5-([1,2, 4] triazol-3-yl-amino-carbonyl), 5- (pyrid-3-yl-amino-carbonyl), 5- (quinolin-3-yl-a) No-carbonyl), 5- (quinolin-5-yl-amino-carbonyl), 5- (quinolin-6-yl-amino-carbonyl), 5- (quinolin-8-yl-amino-carbonyl), 5- ( Isoquinolin-5-yl-amino-carbonyl), 5- (isoquinolin-8-yl-amino-carbonyl), 5- (benzothiazol-6-yl-amino-carbonyl), 5- (benzimidazol-4-yl- Amino-carbonyl), 5- (benzimidazol-5-yl-amino-carbonyl), 5- (1-methyl-benzimidazol-4-yl-amino-carbonyl), 5- (pyrazol-3-yl-amino-) Carbonyl), 5- (5-phenyl-pyrazol-3-yl-amino-carbonyl), 5- (1H-pyrazolo [3,4-d] pyrimidi -4-yl-amino-carbonyl), 5- (1,1-dioxo-benzothiophen-6-yl-amino-carbonyl), 5- (1,2,3,4-tetrahydro-quinolin-1-yl- Amino-carbonyl), 5- (1,2,3,4-tetrahydro-quinolin-1-yl-carbonyl), 5- (1,2,3,4-tetrahydro-isoquinolin-2-yl-carbonyl), 5 -(Pyrid-3-yl), 5- (pyrid-4-yl), 5- (6-methoxy-pyrid-3-yl), 5- (2,3-dihydro-benzo [b] [1,4 Dioxin-6-yl), and 5- (benzo [d] [1,3] dioxol-5-yl).

In another embodiment of the invention, R ² is hydrogen, 5-bromo, 5- (phenyl), 5- (4-fluorophenyl), 5- (4-methoxy-phenyl), 5- (3,4 -Dimethoxy-phenyl), 5- (3,5-dimethoxy-phenyl), 5- (3-cyano-phenyl), 5- (3-carboxy-phenyl), 5- (4-carboxy-phenyl), 5- (4-trifluoromethyl-phenyl), 5- (4-trifluoromethoxy-phenyl), 5- (3,5-di (trifluoromethyl) -phenyl), 5- (2- (aminocarbonyl) -phenyl ), 5- (3- (aminocarbonyl) -phenyl), 5- (4- (aminocarbonyl) -phenyl), 5- (3- (aminosulfonyl) -phenyl), 5- (phenoxy), 5- ( 3,4-Dimetoki -Phenoxy), 5- (phenyl-amino-carbonyl), 5- (3-chlorophenyl-amino-carbonyl), 5- (4-chlorophenyl-amino-carbonyl), 5- (2-fluorophenyl-amino-carbonyl) , 5- (3-fluorophenyl-amino-carbonyl), 5- (4-fluorophenyl-amino-carbonyl), 5- (3-methylphenyl-amino-carbonyl), 5- (4-methylphenyl-amino- Carbonyl), 5- (2-isopropylphenyl-amino-carbonyl), 5- (4-isopropylphenyl-amino-carbonyl), 5- (4-t-butylphenyl-amino-carbonyl), 5- (2-methoxy) Phenyl-amino-carbonyl), 5- (3-methoxyphenyl-amino-carbonyl), 5- (4- Methoxyphenyl-amino-carbonyl), 5- (3,4-difluorophenyl-amino-carbonyl), 5- (3,4-dichlorophenyl-amino-carbonyl), 5- (3,4-dimethylphenyl-amino-carbonyl) ), 5- (2,6-dimethylphenyl-amino-carbonyl), 5- (3,4-dimethoxyphenyl-amino-carbonyl), 5- (3,5-dimethoxyphenyl-amino-carbonyl), 5- ( Naphth-1-yl-amino-carbonyl), 5- (pyrid-3-yl-amino-carbonyl), 5- (quinolin-3-yl-amino-carbonyl), 5- (quinolin-5-yl-amino-) Carbonyl), 5-quinolin-6-yl-amino-carbonyl), 5- (quinolin-8-yl-amino-carbonyl), 5- (isoquino) -5-yl-amino-carbonyl), 5- (isoquinolin-8-yl-amino-carbonyl), 5- (benzothiazol-6-yl-amino-carbonyl), 5- (benzimidazol-4-yl-) Amino-carbonyl), 5- (benzimidazol-5-yl-amino-carbonyl), 5- (1-methyl-benzimidazol-4-yl-amino-carbonyl), 5- (pyrazol-3-yl-amino-) Carbonyl), 5- (5-phenyl-pyrazol-3-yl-amino-carbonyl), 5- (1H-pyrazolo [3,4-d] pyrimidin-4-yl-amino-carbonyl), 5- (1, 1-dioxo-benzothiophen-6-yl-amino-carbonyl), 5- (1,2,3,4-tetrahydro-quinolin-1-yl-amino-cal Nyl), 5- (1,2,3,4-tetrahydro-quinolin-1-yl-carbonyl), 5- (1,2,3,4-tetrahydro-isoquinolin-2-yl-carbonyl), 5- ( Pyrid-3-yl), 5- (pyrid-4-yl), 5- (6-methoxy-pyrid-3-yl), 5- (2,3-dihydro-benzo [b] [1,4] dioxin -6-yl), and 5- (benzo [d] [1,3] dioxol-5-yl).

In another embodiment of the present invention, R ² is 5-bromo, 5- (phenyl), 5- (4-fluorophenyl) 5- (4-methoxy-phenyl) -, 5- (3,4-dimethoxy -Phenyl), 5- (3,5-dimethoxy-phenyl), 5- (3-cyano-phenyl), 5- (3-carboxy-phenyl), 5- (4-carboxy-phenyl), 5- (4 -Trifluoromethyl-phenyl), 5- (4-trifluoromethoxy-phenyl), 5- (3,5-di (trifluoromethyl) -phenyl), 5- (3- (aminocarbonyl) -phenyl), 5- (4- (aminocarbonyl) -phenyl), 5- (3- (aminosulfonyl) -phenyl), 5- (phenoxy), 5- (3,4-dimethoxy-phenoxy), 5- (3-chlorophenyl) -Amino Carbonyl), 5- (4-chlorophenyl-amino-carbonyl), 5- (3-fluorophenyl-amino-carbonyl), 5- (3-methylphenyl-amino-carbonyl), 5- (4-isopropylphenyl-amino) -Carbonyl), 5- (4-tert-butylphenyl-amino-carbonyl), 5- (3-methoxyphenyl-amino-carbonyl), 5- (4-methoxyphenyl-amino-carbonyl), 5- (3 4-difluorophenyl-amino-carbonyl), 5- (3,4-dichlorophenyl-amino-carbonyl), 5- (3,4-dimethylphenyl-amino-carbonyl), 5- (2,6-dimethylphenyl-amino) -Carbonyl), 5- (3,4-dimethoxyphenyl-amino-carbonyl), 5- (naphth-1-yl-a) Mino-carbonyl), 5- (quinolin-3-yl-amino-carbonyl), 5- (quinolin-5-yl-amino-carbonyl), 5- (quinolin-6-yl-amino-carbonyl), 5- ( Quinolin-8-yl-amino-carbonyl), 5- (isoquinolin-5-yl-amino-carbonyl), 5- (isoquinolin-8-yl-amino-carbonyl), 5- (benzothiazol-6-yl-amino) -Carbonyl), 5- (pyrid-3-yl), 5- (pyrid-4-yl), 5- (6-methoxy-pyrid-3-yl), 5- (2,3-dihydro-benzo [b ] [1,4] dioxin-6-yl) and 5- (benzo [d] [1,3] dioxol-5-yl).

In another embodiment of the present invention, R ² is 5- (4-methoxy-phenyl) -, 5- (3,4-dimethoxy-phenyl) -, 5- (3,5-dimethoxy-phenyl) - 5- ( 3-cyano-phenyl), 5- (4-carboxy-phenyl), 5- (3- (aminocarbonyl) -phenyl), 5- (phenoxy), 5- (3,4-dimethoxy-phenoxy), 5- (3-methoxyphenyl-amino-carbonyl), 5- (4-methoxyphenyl-amino-carbonyl), 5- (2,6-dimethylphenyl-amino-carbonyl), 5- (3,4-dimethoxyphenyl-amino) -Carbonyl), 5- (quinolin-3-yl-amino-carbonyl), 5- (quinolin-5-yl-amino-carbonyl), 5- (quinolin-6-yl-amino-carbonyl) 5- (isoquinolin-5-yl-amino-carbonyl), 5- (isoquinolin-8-yl-amino-carbonyl), 5- (pyrid-3-yl), 5- (pyrid-4-yl), 5- (6-methoxy-pyrid-3-yl), 5- (2,3-dihydro-benzo [b] [1,4] dioxin-6-yl), and 5- (benzo [d] [1,3] It is selected from the group consisting of dioxol-5-yl).

In another embodiment of the invention, R ² is selected from the group consisting of 5- (3,4-dimethoxyphenyl) and 5- (3,4-dimethoxyphenyl-amino-carbonyl). In another embodiment of the present invention, R ² is hydrogen.

In one embodiment of the invention, the R ² group is

Bonded at the 5th or 6th position of the core. In another embodiment, the R ² group is

Bonded at the 5th position of the core. In one embodiment of the invention, the R ² group is

Bonded at the 5th or 6th position of the core. In another embodiment, the R ² group is

Bonded at the 5th position of the core.

In one embodiment, the present invention is directed to compounds of formula (I) wherein the stereocenter indicated by the “ ^* ” symbol is present in the (R) configuration. Preferably, the compound of formula (I) is present in the (R) configuration with an enantiomeric excess of about 80% or more, more preferably with an enantiomeric excess of about 90% or more, even more preferably about It is present at an enantiomeric excess of 95% or more, even more preferably at an enantiomeric excess of about 98% or more, and most preferably at an enantiomeric excess of about 99% or more.

In one embodiment, the present invention is directed to compounds of formula (I) wherein the stereocenter indicated by the “ ^* ” mark is present in the (S) configuration. Preferably, the compound of formula (I) is present in the (S) configuration with an enantiomeric excess of about 80% or more, more preferably with an enantiomeric excess of about 90% or more, even more preferably about It is present at an enantiomeric excess of 95% or more, even more preferably at an enantiomeric excess of about 98% or more, and most preferably at an enantiomeric excess of about 99% or more.

In one embodiment, the present invention is directed to compounds of formula (II) wherein the stereocenter indicated by the “ ^* ” mark is present in the (R) configuration. Preferably, the compound of formula (II) is present in the (R) configuration with an enantiomeric excess of about 80% or more, more preferably with an enantiomeric excess of about 90% or more, even more preferably about It is present at an enantiomeric excess of 95% or more, even more preferably at an enantiomeric excess of about 98% or more, and most preferably at an enantiomeric excess of about 99% or more.

In one embodiment, the present invention is directed to compounds of formula (II) wherein the stereocenter indicated by the “ ^* ” mark is present in the (S) configuration. Preferably, the compound of formula (II) is present in the (S) configuration with an enantiomeric excess of about 80% or more, more preferably with an enantiomeric excess of about 90% or more, even more preferably about It is present at an enantiomeric excess of 95% or more, even more preferably at an enantiomeric excess of about 98% or more, and most preferably at an enantiomeric excess of about 99% or more.

  Additional embodiments of the present invention may include variations defined herein (ie,

Any substituent selected for one or more of R ¹ , R ² , L, X, Y, and n) is selected from the complete list as defined herein Includes those independently selected to be independent substituents or any subset of substituents. In another embodiment, the invention is any single compound or a subset of compounds selected from the representative compounds listed in Tables 1-4 below.

Representative compounds of formula (I) of the present invention are as listed in Tables 1-3 below. One of ordinary skill in the art will be able to identify R ² substituents of compounds of formula (I) (including Tables 1-3 below).

It will be appreciated that in describing the position of attachment to the core, the position of the R ² substituent should be indicated according to the following numbering scheme:

Those skilled in the art will recognize that in Tables 1-3 that follow in this specification, in the column heading “R ² ”, the description for #-(substituent) is R ²

It will be further appreciated that the position of the substituent in parenthesis should be indicated following the position attached to the. For example, the notation 5- (3,4-dimethoxy-phenyl) is

3 shows a 3,4-dimethoxy-phenyl group attached at the 5-position of the core.

  Representative compounds of formula (II) of the present invention are as listed in Table 4 below.

In another embodiment, the present invention is a compound of formula (I) having an IC _50, measured according to the procedure described in Biological Example 1, of about 10 μM or less, preferably about 5. It is aimed at compounds that are 0 μM or less, more preferably about 1.0 μM or less, more preferably about 0.5 μM or less, more preferably about 0.1 μM or less.

In another embodiment, the present invention is a compound of formula (II) having an IC _50, measured according to the procedure described in Biological Example 1, of about 10 μM or less, preferably about 5. Aimed at compounds that are 0 μM or less, preferably about 1.0 μM or less, more preferably about 0.5 μM or less, more preferably about 0.1 μM or less.

  As used herein, “halogen” means chlorine, bromine, fluorine and iodine.

As used herein, the term “alkyl”, whether used alone or as part of a substituent, includes straight and branched carbons of 1 to 6 carbon atoms. It is intended to include a chain composition. For example, an alkyl group shall include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and the like. The prefix “C _XY ” where X and Y are integers, when used with alkyl, shall mean a carbon chain composition of X to Y carbon atoms. For example, the term “C _1-4 alkyl” shall mean straight and branched carbon chain compositions of 1 to 4 carbon atoms.

_Those skilled in the art will recognize that the terms “— (alkyl)-” and “— (C _1-4 alkyl)-” are any alkyl carbon chain or C _1-4 alkyl carbon chain, as defined herein. It will be appreciated that the alkyl chain or C _1-4 alkyl chain is divalent and represents an alkyl carbon chain that is further bonded through two points of attachment, preferably through two terminal carbon atoms. Let's go.

As used herein, unless otherwise indicated, the term “halogenated C _1-4 alkyl” is as defined above, preferably substituted with at least one halogen atom, preferably at least one fluorine. It shall mean any C _1-4 alkyl group substituted with an atom. Suitable _{examples, -CF 3, -CCl 3, -CH} 2 -CF 3, -CH 2 CCl 3, -CF 2 -CF 2 -CF 2 but -CF ₃ and the like, without limitation. Similarly, as used herein, unless otherwise indicated, the term “fluorinated C _1-4 alkyl” refers to any C ₁ as defined above, substituted with at least one fluorine atom. _It shall mean _{~ 4} alkyl groups. Suitable examples are _{-CF 3, -CH 2 -CF 3,} -CF 2 -CF 2 -CF 2 -CF 3 but are not limited to, those similar thereto, without limitation. Preferably, the alkyl halide or fluorinated alkyl is —CF ₃ .

As used herein, the term “alkoxy”, whether used alone or as part of a substituent, includes straight and branched chains of 1-6 carbon atoms as described above. The oxygen chain radical of any of the carbon chain compositions of For example, alkoxy radicals include methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentoxy and the like. The prefix “C _XY ” where X and Y are integers, when used with alkoxy, shall mean an oxygen radical of any of the carbon chain compositions of X to Y carbon atoms described above. . For example, the term “C _1-4 alkoxy” shall mean any oxygen ether radical of a linear or branched carbon chain composition of 1 to 4 carbon atoms. Suitable examples include methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and t-butoxy.

As used herein, unless otherwise specified, the term “halogenated C _1-4 alkoxy” is as defined above, preferably substituted with at least one halogen atom, preferably at least one fluorine. It shall mean any C _1-4 alkoxy group substituted with an atom. Suitable _{examples, -OCF 3, -OCCl 3, -OCH} 2 -CF 3, -OCH 2 CCl 3, -OCF 2 -CF 2 -CF 2 but -CF ₃ and the like, without limitation. Similarly, as used herein, unless otherwise indicated, the term “fluorinated C _1-4 alkoxy” refers to any C ₁ , as defined above, substituted with at least one fluorine atom. _It shall mean _{~ 4} alkoxy groups. Suitable _{examples, -OCF 3, -OCH 2 -CF 3} , -OCF 2 -CF 2 -CF 2 -CF 3 but are not limited to, those similar thereto, without limitation. Preferably, the halogenated or fluorinated alkoxy is —OCF ₃ .

As used herein, unless otherwise noted, “aryl” shall refer to unsubstituted carbocylic aromatic groups such as phenyl, naphthyl, and the like. As used herein, unless otherwise specified, “aralkyl” shall mean any C _1-4 alkyl group substituted with an aryl group such as phenyl, naphthyl, and the like. For example, benzyl, phenylethyl-, phenyl-n-propyl-, naphth-1-ylmethyl-, and the like.

As used herein, unless otherwise indicated, the term “C _3-6 cycloalkyl” refers to any stable 3-6 membered monocyclic saturated ring system such as cyclopropyl, cyclobutyl, cyclopentyl, and It shall mean cyclohexyl.

  As used herein, unless otherwise specified, a “5- to 6-membered heteroaryl” contains at least one heteroatom selected from the group consisting of O, N, and S; An arbitrary 5- or 6-membered monocyclic aromatic ring structure optionally containing 1 to 3 additional heteroatoms independently selected from the group consisting of, N, and S. A heteroaryl group can be attached at any heteroatom or carbon atom in the ring so as to provide a stable structure. Examples of suitable heteroaryl groups include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl and the like. It is not limited. Preferred heteroaryl groups include, but are not limited to, thienyl, thiazolyl, pyrazolyl, imidazolyl, pyridyl, and triazolyl.

  As used herein, the term “heterocyclyl” contains at least one heteroatom selected from the group consisting of O, N, and S, optionally from the group consisting of O, N, and S. Any 5- to 7-membered monocyclic, saturated, partially unsaturated, or aromatic cyclic structure containing 1-3 independently selected additional heteroatoms; or O, N, And at least one heteroatom selected from the group consisting of S and optionally containing 1-4 additional heteroatoms independently selected from the group consisting of O, N, and S And any 9-10 membered saturated, partially unsaturated, partially aromatic (including benzo-fused) or aromatic bicyclic ring system. The heterocyclyl group can be attached at any heteroatom or carbon atom in the ring so as to provide a stable structure. Examples of suitable heterocyclyl groups include thienyl, thiazolyl, pyrazolyl, imidazolyl, pyridyl, triazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, 1H-pyrazolo [3,4-d] pyrimidinyl, pyrrolinyl, pyrrolidinyl, Dioxalanyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, indolinyl, chromenyl, 3,4-methylenedioxyphenyl, 1,3-dihydrobenzofuryl, 1, Examples include, but are not limited to, 2,3,4-tetrahydro-quinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl, and the like. . Preferred heterocyclyl groups include thienyl, thiazolyl, pyrazolyl, imidazolyl, pyridyl, triazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, 1H-pyrazolo [3,4-d] pyrimidinyl 1,2,3,4-tetrahydro-quinolinyl, and 1,2,3,4-tetrahydro-isoquinolinyl, but are not limited thereto.

  When a particular group is “substituted” (eg, alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, etc.), that group is one or more selected independently from the list of substituents May have 1 to 5 substituents, preferably 1 to 5 substituents, more preferably 1 to 3 substituents, most preferably 1 to 2 substituents.

  With respect to substituents, the term “independently” means that where more than one such substituent is possible, such substituents may be the same or different from one another.

As used herein, the notation “ ^* ” shall indicate the presence of an asymmetric center. If the compounds of the invention have at least one chiral center, they can accordingly exist as enantiomers. If a compound has more than one chiral center, they can also exist as diastereomers. All such isomers and mixtures thereof are to be considered within the scope of the present invention. Preferably, when the compound is present as an enantiomer, the enantiomer has an enantiomeric excess of about 80% or more, more preferably an enantiomeric excess of about 90% or more, even more preferably about 95% or more. Enantiomeric excess, even more preferably present at an enantiomeric excess of about 98% or greater, and most preferably at an enantiomeric excess of about 99% or greater. Similarly, when the compound is present as a diastereomer, the diastereomer has a diastereomeric excess of about 80% or more, more preferably a diastereomeric excess of about 90% or more, even more preferably about It is present in a diastereomeric excess of 95% or more, even more preferably in a diastereomeric excess of about 98% or more, and most preferably in a diastereomeric excess of about 99% or more.

  Furthermore, some crystalline forms of the compounds of the invention may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds of the present invention can form solvates with water (ie, hydrates) or solvates with common organic solvents, such solvates also It is intended to be included within the scope of the present invention.

Under standard nomenclature used throughout this disclosure, the end of the designated side chain is described first, followed by adjacent functional groups toward the point of attachment. Thus, for example, a “phenyl C ₁ -C ₆ alkylaminocarbonyl C ₁ -C ₆ alkyl” substituent refers to a group of the following formula:

  Abbreviations used in the specification, particularly in the schemes and examples, are as follows:

  As used herein, unless otherwise noted, the term “isolated form” refers to any solid mixture, solvent system or biology in which the compound is in combination with another compound or compounds. It means to exist in a form separated from the physical environment. In one embodiment, the compound of formula (I) is prepared as an isolated form. In another embodiment, the compound of formula (II) is prepared as an isolated form.

  As used herein, unless otherwise specified, the term “substantially pure compound” means that the mole percent of impurities in the isolated compound is less than about 5 mole percent, preferably about 2 mole percent. Less than, more preferably less than about 0.5 mole percent, and most preferably less than about 0.1 mole percent. In one embodiment, the compound of formula (I) exists as a substantially pure compound. In another embodiment, the compound of formula (II) exists as a substantially pure compound.

  As used herein, unless otherwise indicated, the term “substantially free of the corresponding salt form” when used to describe a compound of formula (I) ) Of the corresponding salt form in the base of less than about 5 mole percent, preferably less than about 2 mole percent, more preferably less than about 0.5 mole percent, and most preferably less than about 0.1 mole percent. It means that there is. In one embodiment, the compound of formula (I) exists in a form substantially free of the corresponding salt form. In another embodiment, the compound of formula (II) exists in a form substantially free of the corresponding salt form.

  As used herein, unless otherwise indicated, terms such as “treat”, “treatment” and the like are intended for the subject or patient (preferably a mammal, more preferably) for the treatment of a disease, condition or disorder. The administration and care of humans) and also includes administration of the compounds of the present invention for the prevention of the onset of symptoms or complications, the alleviation of symptoms or complications, or the elimination of a disease, condition or disorder .

  As used herein, unless stated otherwise, the term “prevention” refers to (a) a reduction in the frequency of one or more medical conditions, (b) a decrease in the severity of one or more medical conditions, (c And / or (d) delay or avoid the onset of further disease states and / or (d) the development of disease or pathology.

  When the present invention is directed to a prophylactic method, a patient in need of this method (ie, a patient in need of prophylaxis) experiences or exhibits at least one symptom of a disorder, disease or condition to be prevented. One skilled in the art will appreciate that any subject or patient (preferably a mammal, more preferably a human) is included. In addition, patients in need of this method additionally do not show any symptoms of the disorder, disease or condition to be prevented, but doctors who are at risk of developing those disorders, diseases or conditions, It can also be a patient (preferably a mammal, more preferably a human) being viewed by a clinician or other medical professional. For example, as a result of a patient's medical history, including, but not limited to, a family calendar, individual predisposition, a combined (complicated) disorder or combined (complicated) symptom, genetic testing, etc., the patient may have a disorder, disease or condition. May be deemed to be at risk (and therefore need to be prevented or prevented).

  As used herein, the term “patient” refers to an animal, preferably a mammal, most preferably a human, that is the subject of treatment, observation or experiment. Preferably, the patient experiences and / or exhibits at least one condition of the disease or disorder to be treated and / or prevented.

  As used herein, the term “therapeutically effective amount” refers to a tissue that includes alleviation of the symptoms of the disease or disorder being treated, as sought by a researcher, veterinarian, physician, or other clinician. The amount of active compound or pharmaceutical agent that elicits a biological or pharmaceutical response within a system, animal, or human.

  As used herein, the term “composition” refers to a product containing a specific component in a specific amount, as well as any product resulting from a specific amount of combination of specific components, either directly or indirectly. Intended to include.

As used herein, the term “DPP-1-mediated disorder” is intended to include any condition, disease, or disorder that can be mediated through inhibition of DPP-1 activity. One skilled in the art will recognize that disorders mediated by DPP-1 include, but are not limited to:
(A) Airway disorders: bronchial, allergic, endogenous, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-induced), and intermittent and persistent, including dust-induced asthma Airflow obstructive disorders, including asthma of all severity, and other causes of airway hypersensitivity reactions; chronic obstructive pulmonary disease (COPD); bronchitis including infectious and eosinophilic bronchitis; emphysema; Bronchiectasis; cystic fibrosis; sacroidosis; farmer's lung and related diseases; hypersensitivity pneumonitis; idiopathic fibrotic alveolitis, idiopathic interstitial pneumonia Pulmonary fibrosis, including fibrosis and chronic infections including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the pulmonary vasculature; and Pulmonary hypertension Antitussive activity including treatment of chronic cough associated with airway inflammation and secretion, and iatrogenic cough; acute and chronic rhinitis including drug-induced rhinitis and vasomotor rhinitis; including neurorhinitis (hay fever) Perennial and seasonal allergic rhinitis; nasal polyposis; acute viral infections including colds and infections with respiratory syncytial viruses, influenza, coronaviruses (including SARS) and adenoviruses (b) skin disorders: psoriasis, Atopic dermatitis, contact dermatitis, or other eczema dermatoses, and delayed-type hypersensitivity reactions; vegetative and photosensitivity dermatitis; seborrheic dermatitis (dermatistis), shingles ( herptiformis) dermatitis, lichen planus, lichen slerosus et atrophica, pyoderma gangrenosum, cutaneous sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, Urticaria, angioderma, vasculitis, toxid erythmas, cutaceous eosinophilia, alopecia areata, androgenetic alopecia, sweet syndrome, Weber-Christian syndrome, multiple Erythema multiforma; both infectious and incomplete cellulitis; panniculitis; cutaceous lymphomas, nonmelanoma skin cancer and other dysmorphic lesions; including fixed drug eruption Drug-induced disorders (c) Eye disorders: blepharitis and conjunctivitis, including perennial and spring allergic conjunctivitis; irisitis; anterior and posterior uveitis; choroiditis; Or inflammatory disorders; opthalmitis including sympathetic opthalmitis; sarcoidosis; viral, fungal and bacterial infections (d) genitourinary disorders: interstitial nephritis And yarn ball Nephritis, including glomerulonephritis; nephritis syndrome; cystitis, including acute and chronic (interstitial) cystitis, and Hanner ulcers; acute and chronic urethritis, prostatitis, epididysitis, ovitis, and eggs Vasculitis; vulvovaginitis; Peyronie's disease; erectile dysfunction (e) Allograft rejection disorder: Acute and chronic, eg, following kidney, heart, liver, lung, bone marrow, skin, or corneal transplant, or for blood transfusion Continued; or chronic graft-versus-host disease (f) rheumatoid arthritis, irritable bowel syndrome, systemic lupus erythematosus, multiple sclerosis, Hashimoto's thyroiditis, Graves' disease, Addison's disease, diabetes mellitus, idiopathic thrombocytopenia Autoimmune and allergic disorders, including (thrombocytopaenic) purpura, eosinophilic fasciitis, hyper-IgE syndrome, antiphospholipid syndrome, and Sazary syndrome (g) Cancer: prostate General cancer, including breast, lung, ovary, pancreas, intestine and colon, and gastric cancer, skin and brain tumors and malignant tumors (including leukemia) that affect the bone marrow, and lymphocyte proliferation such as Hodgkin and non-Hodgkin lymphoma Cancer including systemic treatment; prevention and treatment of metastatic disease and tumor recurrence, and cancer including paraneoplstic syndrome (h) Infectious diseases: genital warts, common warts, plantar warts, Hepatitis B, hepatitis C, herpes simplex virus, molluscum contagiosum, smallpox, human immunodeficiency virus (HIV), human papilloma virus (HPV), cytomegalovirus (CMV), varicella zoster virus (zoser) virus ( VZV), rhinovirus, adenovirus, coronavirus, influenza, parainfluenza and other viral diseases; tubercuavium, Hanse Bacterial diseases such as fungal diseases; fungal diseases, chlamydia, candida, aspergillus, cryptococcal meningitis, pneumocystis carini, cryptosporidiosis, histoplasmosis, toxoplasmosis, trypanosoma infection, leishmaniasis, etc. Other infectious diseases.

  In another embodiment, the present invention is directed to a method for the treatment and / or prevention of a DDP-1-mediated disorder, wherein the DPP-1-mediated disorder is chronic obstructive pulmonary disease (COPD), asthma, acute Selected from the group consisting of pulmonary trauma, adult respiratory distress syndrome, abdominal or thoracic aneurysm, rheumatoid arthritis, osteoarthritis, multiple sclerosis, sepsis, and taxoplasmosis.

  In another embodiment, the present invention is directed to a method for the treatment and / or prevention of a DDP-1-mediated disorder, wherein the DPP-1-mediated disorder is rheumatoid arthritis, asthma, chronic obstructive pulmonary disease ( COPD), sepsis, irritable bowel disease, cystic fibrosis, and abdominal aortic aneurysm.

  When given more broadly in the written description, terms such as “react” and “reacted” are (a) the actually described form of such chemical, and (b) when the compound is named. As used herein with reference to a chemical that is any one of these forms of chemical in the medium under consideration.

  Those skilled in the art will recognize that unless otherwise stated, the reaction steps are performed according to known methods under suitable conditions to yield the desired product. Those skilled in the art will further recognize that in the specification and claims presented herein, a reagent or reagent class / type (eg, base, solvent, etc.) is cited in more than one step of the method. It will be appreciated that the individual reagents are independently selected for each reaction step and may be the same or different from each other. For example, if the two steps of the method list an organic or inorganic base as a reagent, the organic or inorganic base selected for the first step may be the same or different from the organic or inorganic base of the second step. Good. Furthermore, those skilled in the art will recognize that the reaction steps of the present invention can be performed in a variety of solvents or solvent systems, and that such reaction steps can also be performed in a suitable solvent or mixture of solvent systems. Will.

  To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term “about”. Whether or not the term “about” is explicitly used, all amounts stated herein are meant to refer to their actual values, and approximate such values by experiment and / or measurement conditions. Is also meant to refer to an approximation of such a value reasonably inferred based on ordinary skill in the art.

  To provide a more concise description, some of the quantitative expressions herein are set forth as a range of about amount X to about amount Y. Whether or not a range is described, it is understood that the range is not limited to the stated upper and lower limits, but includes the entire range of about amount X to about amount Y, or any range therein. The

  Examples of suitable solvents, bases, reaction temperatures, and other reaction parameters and components are described in detail herein below. Those skilled in the art will recognize that the listing of the above examples is in no way intended to limit the invention described in the claims below and should not be so construed.

  As used herein, unless otherwise noted, the term “aprotic solvent” shall mean any solvent that does not produce protons. Suitable examples include, but are not limited to, DMF, 1,4-dioxane, THF, acetonitrile, pyridine, dichloroethane, dichloromethane, MTBE, toluene, acetone and the like.

  As used herein, unless otherwise indicated, the term “leaving group” shall mean a charged or uncharged atom or group that leaves during a substitution or displacement reaction. Suitable examples include, but are not limited to Br, Cl, I, mesylate, tosylate and the like.

As used herein, unless otherwise noted, the term “nitrogen protecting group” can be attached to a nitrogen atom to prevent the nitrogen atom from participating in the reaction and It shall mean a group which can be easily removed later. Suitable nitrogen protecting groups, carbamates - formula -C (O) OR [wherein, R is, for example, methyl, ethyl, t- butyl, benzyl, _{phenylethyl, CH 2 = CH-CH 2} - , and the like] A group of amide-formula-C (O) -R ′ [wherein R ′ is, for example, methyl, phenyl, trifluoromethyl, etc.]; N-sulfonyl derivatives—formula —SO ₂ —R ″ [wherein , R ″ is, for example, a group of tolyl, phenyl, trifluoromethyl, 2,2,5,7,8-pentamitylchroman-6-yl-, 2,3,6-trimethyl-4-methoxybenzene, etc.] For example, but not limited to. Other suitable nitrogen protecting groups are T.I. W. Greene & P. G. M.M. It can be found in textbooks such as Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

  As used herein, unless otherwise noted, the term “oxygen protecting group” can be attached to an oxygen atom to prevent such oxygen atom from participating in the reaction and after the reaction. Means a group which can be easily removed. Suitable oxygen protecting groups include, but are not limited to, acetyl, benzoyl, t-butyl-dimethylsilyl, trimethylsilyl (TMS), MOM, THP, and the like. Other suitable oxygen protecting groups are T.I. W. Greene & P. G. M.M. It can be found in textbooks such as Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

  One skilled in the art will recognize that the reaction steps of the present invention can be performed in a variety of solvents or solvent systems, and that the reaction steps can also be performed in a suitable solvent or mixture of solvent systems.

  If the process for the preparation of the compounds according to the invention results in a mixture of stereoisomers, these isomers can be separated by conventional techniques such as, for example, preparative chromatography. The compounds may be prepared in racemic form or the individual enantiomers can be prepared either by enantioselective synthesis or resolution. The compound is salted with optically active acids such as, for example, standard techniques such as (−)-di-p-toluoyl-D-tartaric acid and / or (+)-di-p-toluoyl-L-tartaric acid. After forming the diastereomeric pair by formation, fractional crystallization and free base regeneration can be performed to resolve the constituent enantiomers. Compounds can also be resolved by formation of diastereomeric esters or amides followed by chromatographic separation and removal of chiral auxiliary groups. Alternatively, the compounds may be resolved using a chiral HPLC column.

In addition, chiral HPLC against standards can be used to determine enantiomeric excess (% ee). The enantiomeric excess ratio can be calculated as follows.
[(R mol-S mol) / (R mol + S mol)] × 100%
In the formula, R mole and S mole are R and S mole fractions in the mixture such that R mole + S mole = 1. Alternatively, the enantiomeric excess can be calculated from the specific rotation of the desired enantiomer and the prepared mixture as follows.
ee = ([α-obs] / [α-max]) × 100

  During any process of preparing a compound of the invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any molecule involved. This is described in Protective Groups in Organic Chemistry, ed. J. et al. F. W. McOmie, Plenum Press, 1973 and T.W. W. Greene & P. G. M.M. It may be achieved using conventional protecting groups such as those described in Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting group may be removed at a subsequent convenient stage using methods known in the art.

  For use in medicine, the salts of the compounds of the invention refer to non-toxic "pharmaceutically acceptable salts." However, other salts may be useful in the preparation of the compounds according to the invention or their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds include acid addition salts, which include, for example, a solution of the compound in hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, It can be formed by mixing with a solution of a pharmaceutically acceptable acid such as tartaric acid, carbonic acid, or phosphoric acid. In addition, when the compound of the present invention has an acidic moiety, suitable pharmaceutically acceptable salts thereof include alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; Salts formed with other organic ligands, such as quaternary ammonium salts can be included. Thus, representative pharmaceutically acceptable salts include, but are not limited to: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate Salt, borate, bromide, calcium edetate, cansylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edicylate, estrate, esylate, fumarate, Glycceptate, gluconate, glutamate, glycolylarsanilate, hexyl resorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthalate, iodide, isothionate, lactate, Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate, Methyl bromide, Methyl nitrate, Methyl sulfate, Mu Cocoates, napsylates, nitrates, N-methylglucamine ammonium salts, oleates, pamoates (embonates), palmitates, pantothenates, phosphates / diphosphates, polygalacturolones , Salicylates, stearates, sulphates, basic acetates, succinates, tannates, tartrate, theocurate, tosylate, triethiodide and valerate.

  Representative acids that can be used to prepare pharmaceutically acceptable salts include, but are not limited to: acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid , Ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S) -camphor-10-sulfonic acid, capric acid , Caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisin Acid, glucoheptonic acid, D-gluconic acid, D-glucoronic acid, L-glutamic acid, α-oxo -Glutaric acid, glycolic acid, hipuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±) -DL-lactic acid, lactobionic acid, maleic acid, (-)-L-apple Acid, malonic acid, (±) -DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid , Orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebaic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+) -L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, and undecylenic acid.

  Representative bases that can be used in the preparation of pharmaceutically acceptable salts include, but are not limited to: ammonia, L-arginine, venetamine, benzathine, calcium hydroxide, choline, deanol. , Diethanolamine, diethylamine, 2- (diethylamino) -ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesium hydroxide, 4- (2-hydroxyethyl) -morpholine, piperazine Potassium hydroxide, 1- (2-hydroxyethyl) -pyrrolidine, secondary amine, sodium hydroxide, triethanolamine, tromethamine, and zinc hydroxide.

  The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs are functional derivatives of the compounds that can be readily converted in vivo to the required compound. That is, in the methods of treatment of the present invention, the term “administration” refers to the various disorders described in vivo using a specifically disclosed compound or not specifically disclosed but administered to a patient. Treatment with a compound that converts to a specific compound should be included. General procedures for selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, H.M. Bundgaard, Elsevier, 1985.

  L is

Compounds of formula (I) can be prepared according to the process outlined in Scheme 1.

Accordingly, a suitably substituted compound of formula (V) (wherein LG ¹ is a suitably selected leaving group of bromo, chloro and iodine, preferably bromo, preferably a known compound or known method) Prepared compound) in the presence of a suitably selected catalyst such as Pd (PPh ₃ ) ₂ Cl ₂ , Pd (OAc) ₂ Cl ₂ , Pd (dppf) Cl ₂ , and Pd (dppp) Cl _{2. ; Na 2 CO 3, K 2} CO 3, Cs 2 CO 3 or the like suitably in the presence of selected bases; 1,4-dioxane, DMF, and aprotic solvents suitably selected such as toluene In; reacting with a compound of formula (VI) (a known compound or a compound prepared by a known method) which is a suitably substituted boronic acid to give a compound corresponding to formula (VII).

In the presence of a suitably selected binder such as HOBt in combination with a compound of formula (VII) with HBTU, HATU, and EDC; in the presence of a suitably selected organic base such as TEA, DIPEA, and pyridine. Optionally in the presence of a catalyst such as DMAP; in a suitably selected organic solvent such as DMF, DCM, and NMP; suitably substituted compound of formula (VIII) wherein PG ¹ is And a suitably selected nitrogen protecting group such as BOC and CBz, known compounds or compounds prepared by known methods) to give compounds corresponding to formula (X).

Alternatively, a suitably substituted compound of formula (V) (wherein LG ¹ is a suitably selected leaving group such as bromo, chloro and iodine, preferably bromo, preferably a known compound or known In the presence of a suitably selected binder such as HOBt in combination with HBTU, HATU, and EDC; a suitably selected organic base such as TEA, DIPEA, and pyridine. In the presence; optionally in the presence of a catalyst such as DMAP; in a suitably selected organic solvent such as DMF, DCM, and NMP; suitably substituted compound of formula (VIII) (PG ¹ is Reaction with a suitably selected nitrogen protecting group such as BOC and CBz, known compounds or compounds prepared by known methods, to give compounds corresponding to formula (IX).

The compound of formula (IX) is prepared in the presence of a suitably selected catalyst such as Pd (PPh ₃ ) ₂ Cl ₂ , Pd (OAc) ₂ Cl ₂ , Pd (dppf) Cl ₂ , and Pd (dppp) Cl _2. In the presence of a suitably selected base such as Na ₂ CO ₃ , K ₂ CO ₃ , and Cs ₂ CO ₃ ; suitably selected aprotic such as 1,4-dioxane, DMF, and toluene Reaction with a compound of formula (VI) (a known compound or a compound prepared by a known method) which is a suitably substituted boronic acid to give a compound corresponding to formula (X).

The compound of formula (X) is deprotected according to known methods to give the compound corresponding to formula (Ia). For example, where PG ¹ is BOC, the compound of formula (X) is reacted with a suitably selected acid such as HCl and TFA in a suitably selected solvent such as DCM and diethyl ether. To deprotect.

One skilled in the art will recognize that in the case of a compound of formula (Ia) where X is N (R ^B ), the compound may be prepared as described above or alternatively as a corresponding compound where X is NH. It will be appreciated that it can then be further reacted with a suitably selected alkylating agent according to known methods.

Compounds of formula (I) where L is — (CH ₂ ) ₂ -3-NH— may be prepared according to the process outlined in Scheme 2 below.

Thus, the presence of a suitably selected binder such as HOBt in combination with a suitably substituted compound of formula (XI) (known compound or compound prepared by a known method) with HBTU, HATU, and EDC Under; in the presence of a suitably selected organic base such as TEA, DIPEA, and pyridine; in a suitably selected organic solvent such as DMF, DCM, and NMP; suitably substituted formula (VIII) (Wherein PG ¹ is a suitable nitrogen protecting group such as BOC and CBz, known compounds or compounds prepared by known methods) to give compounds corresponding to formula (XII) .

The compound of formula (XII) is deprotected according to known methods to give the compound corresponding to formula (Ib). For example, a compound of formula (XII) where PG ¹ is BOC is deprotected by reacting with a suitably selected acid such as HCl and TFA in a suitably selected solvent such as DCM and diethyl ether. Can be based.

Compounds of formula (I) wherein Y is CH, X is N (R ^B ) and L is — (CH ₂ ) _2-3- NH— were prepared according to the process outlined in Scheme 3 below. Can be done.

  Thus, suitably substituted compounds of formula (VIII) (wherein PG1 is a suitably selected nitrogen protecting group such as Boc, Cbz, and trifluoroacetyl, prepared by known compounds or known methods In the presence of a suitably selected binder such as HOBt in combination with HBTU, HATU, and EDC; in the presence of a suitably selected organic base such as TEA, DIPEA, and pyridine; Optionally in the presence of a catalyst such as DMAP; in a suitably selected organic solvent such as DMF, DCM, and NMP; a compound of formula (XIII) (a known compound or a compound prepared by a known method) To obtain a compound corresponding to (XIV).

In the presence of a suitably selected palladium catalyst such as Pd (PPh ₃ ) ₄ , PdCl ₂ (PPh ₃ ) ₂ , and Pd (PhCN) ₂ Cl ₂ ; in the presence of Cul In a suitably selected solvent such as diethylamine and DMF; a suitably substituted compound of formula (XV) wherein LG ² is a leaving group such as iodine, bromo and chloro; A compound prepared by known methods) to give a compound corresponding to formula (XVI).

The compound of formula (XVI) is subjected to ring-opening conditions, more specifically of a suitably selected catalyst such as Pd (PhCN) ₂ Cl ₂ and Pd (PPh ₃ ) ₄ , PdCl ₂ (PPh ₃ ) ₂ In the presence; in a suitably selected solvent such as DMF and diethylamine; react; to obtain the compound corresponding to formula (XVII).

  A compound of formula (XVII) in the presence of a suitably selected base such as NaH; in a suitably selected solvent such as DMF, THF and diethyl ether; Optionally reacting with a compound of formula (XVII) to give a compound corresponding to formula (XIX).

The compound of formula (XVII) or the compound of formula (XIX) is deprotected to remove the PG ¹ group according to known methods to give the compound corresponding to formula (Ic). For example, a compound of formula (XVII) or a compound of formula (XVIII) (wherein PG ¹ is —C (O) —CF ₃ ) in a suitably selected solvent such as THF and methanol; Reaction with a suitably selected base such as KOH; to obtain a compound corresponding to formula (Ic).

One skilled in the art will recognize that a compound of formula (I) wherein R ² is —C (O) —NR ^C R ^D or —C (O) —NH—Q is a binder such as BOP-Cl and HATU. In the presence of a suitably selected base such as TEA and DIPEA in a suitably selected organic solvent such as DCM, acetonitrile and THF, a suitably selected amine (formula NHR ^C R ^D or Prepared from a compound corresponding to formula (I) in which R ² is —C (O) OH by reacting with a known compound which is a compound of NH ₂ -Q or a compound prepared by a known method). You will recognize that it can be done.

Those skilled in the art, a compound (Y is CH of formula (I), X is N (R ^B), L is - (CH ₂₎ 2~3 -NH- and and, R ² is -O-Q ) Using a compound of formula (XXVI) instead of a compound of formula (XV) according to the process outlined in Scheme 3 above,

By reacting as described above, a compound corresponding to formula (XXVII) is obtained,

The compound of formula (XXVII) is then selected in the presence of CuI; in the presence of a suitably selected base such as Cs ₂ CO ₃ and K ₂ CO ₃ ; suitably selected such as 1,4-dioxane and THF Reaction with a suitably substituted compound of formula Q-OH to obtain a compound corresponding to formula (XXVIII)

The compound of formula (XXVIII) is then deprotected according to known methods to remove the PG ¹ protecting group and the desired compound of formula (I) (Y is CH and X is N (R ^B ) There, L is - (CH ₂₎ 2~3 -NH- and and by R ² to obtain a a a) -O-Q, will further recognize that can be similarly prepared.

Compounds of formula (I) wherein Y is CH, X is N (R ^B ) and L is —CH ₂ CH ₂ CH ₂ —NH— are outlined in Scheme 4 below. Can be prepared according to the process.

Thus, suitably substituted compounds of formula (XV) (wherein LG2 is a suitably selected leaving group such as iodine, bromo, and chloro, prepared by known compounds or known methods Compound) in the presence of a suitably selected palladium catalyst such as Pd (PPh ₃ ) ₄ , PdCl ₂ (PPh ₃ ) ₂ and Pd (PhCN) ₂ Cl ₂ ; in the presence of CuI; diethylamine and DMF etc. A compound of formula (XX) wherein PG ² is a suitably selected nitrogen protecting group such as BOC, CBz and —C (O) CF ₃ Alternatively, it is reacted with a known method (for example by protecting the compound of formula (XIII) according to the known method) to give a compound corresponding to formula (XXI).

The compound of formula (XXI) is subjected to ring-opening conditions, more specifically of a suitably selected catalyst such as Pd (PhCN) ₂ Cl ₂ , Pd (PPh ₃ ) ₄ and PdCl ₂ (PPh ₃ ) ₂ . In the presence; reaction in a solvent such as DMF and diethylamine gives the compound corresponding to formula (XXII).

The compound of formula (XXII) is deprotected according to known methods to give the compound corresponding to formula (XXIII). For example, a compound of formula (XXII) where PG ² is BOC is reacted with a suitably selected acid such as HCl and TFA in a suitably selected organic solvent such as DCM and 1,4-dioxane. By deprotection.

In the presence of a suitably selected binder such as HOBt combined with a compound of formula (XXIII) in combination with HBTU, HATU and EDC; in the presence of a suitably selected organic base such as TEA, DIPEA and pyridine. Optionally in the presence of a catalyst such as DMAP; in a suitably selected organic solvent such as DMF, DCM, and NMP; suitably substituted compound of formula (VIII) wherein PG ¹ is , A suitably selected nitrogen protecting group such as BOC, CBz, and —C (O) CF ₃ , a known compound or a compound prepared by a known method) and corresponds to formula (XXIV) A compound is obtained.

The compound of formula (XXIV) is deprotected according to known methods to give the compound corresponding to formula (Id). For example, a compound of formula (XXIV) where PG ¹ is BOC is reacted with a suitably selected acid such as HCl and TFA in a suitably selected organic solvent such as DCM and 1,4-dioxane. By deprotection.

Those skilled in the art, compounds of formula (I) (wherein, L is a _{-CH 2 CH 2 CH 2 -NH-,} Y is CH, X is N (R ^B, is wherein R ^B Can be prepared by reacting a compound of formula (XXIV) with a suitably selected alkylating agent, as described above, and the resulting product can be deprotected according to known methods It will be appreciated that it can be based.

Compounds of formula (I), wherein L is — (CH ₂ ) _2-3 —N (R ^A ) —, where R ^A is other than hydrogen, are as outlined in the above scheme. Suitably substituted compound of formula (XXV) (wherein W is hydrogen, known compounds or compounds prepared by known methods)

By selecting and using in place of the compound of formula (XIII) in Scheme 3; or alternatively, a suitably substituted compound of formula (XXV), wherein W is such as BOC, CBz and —C (O) CF ₃ A nitrogen protecting group, a known compound or a compound prepared by a known method, can be similarly prepared by selecting and using in place of the compound of formula (XX) in Scheme 4 above.

Compounds of formula (II), wherein L is —CH ₂ CH ₂ CH ₂ —N (R ^A ) —, can be prepared according to the procedure outlined in Scheme 5 below.

Thus, a suitably substituted compound of formula (VIII) wherein PG ¹ is a suitably selected nitrogen protecting group such as BOC, CBz and —C (O) CF ₃ Compounds prepared by known methods) in the presence of a suitably selected binder such as HOBt in combination with HBTU, HATU and EDC; a suitably selected organic base such as TEA, DIPEA and pyridine Optionally in the presence of a catalyst such as DMAP; in a suitably selected organic solvent such as DMF, DCM, and NMP; suitably substituted compounds of formula (C) (known Compound or a compound prepared by known methods) to give a compound corresponding to formula (CI).

The compound of formula (CI), Pd (OAc) 2, Pd (PPh 3) 4 and PdCl ₂ (PPh _{3) 2} or the like suitably in the presence of selected palladium catalyst; P (o-tolyl) ₃ and In the presence of a suitably selected trivalent organophosphorous agent such as PPh ₃ ; in the presence of a suitably selected base such as TEA, DIPEA, and pyridine; such as acetonitrile, DMF, and toluene In a suitably selected organic solvent; reacting with a suitably substituted compound of formula (CII) wherein LG ³ is a suitably selected leaving group such as bromo, chloro and iodine To obtain a compound corresponding to formula (CIII).

  Reacting a compound of formula (CIII) with a hydrogen source such as hydrogen gas in the presence of a suitably selected catalyst such as Pd / C; in a suitably selected organic solvent such as methanol and ethanol; A compound corresponding to (IIa) is obtained.

One skilled in the art will recognize that a compound of formula (II), wherein L is —CH ₂ CH ₂ —N (R ^A ) —, is suitably substituted according to the procedure outlined in Scheme 5 above. ) Compounds

Similarly, by selecting and using (wherein PG ⁰ is a suitably selected nitrogen protecting group) instead of the compound of formula (C), a compound corresponding to formula (IIb) is obtained. It will be appreciated that can be prepared.

One skilled in the art will recognize that a compound of formula (II), wherein X is N (R ^B ), is suitably substituted as described in Scheme 5 above.

Where PG ⁴ is a suitably selected nitrogen protecting group such as BOC, CBz, and —C (O) CF _3, etc., selected and used in place of the compound of formula (CII), as described above. It will be further appreciated that it can be similarly prepared by reacting to obtain a compound corresponding to formula (CVI).

  The compound of formula (CVI) is then further optionally substituted by reacting with a suitably substituted alkylating agent according to known methods, either sequentially or simultaneously deprotected and then suitably substituted. The compound corresponding to IIa) is obtained.

  The present invention further includes pharmaceutical compositions containing one or more compounds of formula (I) and / or one or more compounds of formula (II) and a pharmaceutically acceptable carrier. A pharmaceutical composition containing one or more of the compounds of the invention described herein as an active ingredient is prepared by thoroughly mixing the compound (s) with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. can do. The carrier may take a wide variety of forms depending on the desired route of administration (eg, oral, parenteral). Thus, in liquid oral formulations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, colorants, and the like, For solid oral formulations such as powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrants and the like. Solid oral preparations may be coated with a substance such as sugar or enteric coated to control the major site of absorption. For parenteral administration, the carrier usually consists of sterile water and other ingredients may be added for increased solubility or storage. Injectable suspensions or solutions may also be prepared using aqueous carriers with suitable additives.

  In order to prepare the pharmaceutical composition of the present invention, one or more compounds of the present invention as active ingredients are mixed well with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, and the carrier is used in the formulation desired for administration. A wide variety of forms are possible, depending on the form, eg, oral or parenteral, such as intramuscularly. Any conventional pharmaceutical medium can be used in preparing the composition into an oral dosage form. Thus, for example, in liquid oral formulations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, colorants, etc., powders For solid oral formulations such as capsules, caplets, gelcaps and tablets, suitable carriers and additives include starch, sugar, diluent, granulating agent, lubricant, binder, disintegrant, etc. It is done. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets can be sugar coated or enteric coated by standard techniques. Parenteral carriers usually contain sterile water, but may contain other ingredients for purposes such as to aid solubility or for storage. Injectable suspensions can also be prepared, in which case appropriate liquid carriers, suspending agents and the like can be employed. The pharmaceutical compositions herein contain the amount of active ingredient necessary to deliver the above-mentioned effective dosage per dosage unit, for example per tablet, capsule, powder, injection, teaspoon, etc. To do. The pharmaceutical compositions herein are about 0.01 to about 1,000 mg or any amount therein, for example per tablet, capsule, powder, injection, suppository, teaspoon, etc. Or containing a range of active ingredients and will be applied at a dosage of about 0.01 to about 100 mg / kg / day, or any amount or range therein. However, the dosage may vary depending on the patient's requirements, the severity of the condition being treated, and the compound used. Either daily administration or use of subsequent post-periodic administration can be used.

  Preferably these compositions are for oral, parenteral, intranasal, sublingual or rectal administration, or administration by inhalation or insufflation, eg tablets, pills, capsules, powders, granules, sterile parenteral solutions Or a unit dosage form in the form of a suspension, metered aerosol or liquid propellant, drop, ampoule, autoinjector or suppository. Alternatively, the composition can be given in a form suitable for administration once a week or once a month, for example, an insoluble salt of the active compound, such as a decanoate salt, for a depot formulation for intramuscular injection. Can be adapted to provide. For the preparation of solid compositions such as tablets, the main active ingredient is a pharmaceutical carrier such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gum. These are mixed with conventional tableting ingredients and other pharmaceutical diluents such as water to form solid pre-formulated compositions containing a homogeneous mixture of the compounds of the invention or a pharmaceutically acceptable salt thereof. When these pre-formulated compositions are referred to as homogeneous, the active ingredient is distributed throughout the composition so that the composition can be easily subdivided into equally effective dosage forms such as tablets, pills and capsules. It means that it is uniformly dispersed. This pre-preform composition is then subdivided into unit dosage forms of the type described above containing from 0.01 to about 1,000 mg of the active ingredient of the present invention. The tablets or pills of the new composition can be coated or otherwise compounded to provide a dosage form that provides a sustained action benefit. For example, a tablet or pill can comprise an inner shell dosage component and an outer dosage component, the latter being in a form that wraps around the former. The two components can be separated by an enteric layer that resists disintegration in the stomach and allows its inner core component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids along with materials such as shellac, cetyl alcohol and cellulose acetate.

  Liquid forms that can incorporate the novel compositions of the invention by oral administration or infusion include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and cottonseed oil, sesame oil, coconut oil or peanut oil. Flavored emulsions containing edible oils, and elixirs and similar pharmaceutical excipients. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.

  The treatment methods described in the present invention may also be performed using a pharmaceutical composition comprising any compound as defined herein and a pharmaceutically acceptable carrier. The pharmaceutical composition contains from about 0.01 mg to about 1,000 mg of compound in any amount or range therein, preferably from about 1.0 to 500 mg of compound in any amount or range therein. It can be configured in any form suitable for the mode of administration chosen. Carriers include necessary and inert pharmaceutical excipients including, but not limited to, binders, suspending agents, lubricants, flavoring agents, sweetening agents, preservatives, dyes, and coatings. Compositions suitable for oral administration include solid forms such as pills, tablets, caplets, capsules (including rapid release, timed release and sustained release formulations, respectively), granules, and powders, as well as solutions, Liquid forms such as syrups, elixirs, and suspensions are included. Forms useful for parenteral administration include sterile solutions, emulsions and suspensions.

  Advantageously, the compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of 2, 3, or 4 times per day. May be. Furthermore, the compounds of the present invention can be administered via topical use of a suitable nasal vehicle or by intranasal dosage forms via a transdermal skin patch, well known to those skilled in the art. To be administered in the form of a transdermal delivery system, dosage management is, of course, continuous rather than intermittent throughout the dosage regimen.

  For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. In addition, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture as desired or necessary. Suitable binders include natural sugars such as starch, gelatin, glucose or β-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium oleate, sodium stearate, magnesium stearate , Sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum and the like.

  Liquids are formed as suitably flavored suspending or dispersing agents such as synthetic and natural gums (eg, tragacanth, acacia, methylcellulose, etc.). For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.

  For preparing the pharmaceutical compositions of the invention, the compound of formula (I) as the active ingredient is intimately mixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, but the carrier is administered (eg, orally or Depending on the form of formulation desired for parenteral), it can take a wide variety of forms. Suitable pharmaceutically acceptable carriers are well known in the art. Some descriptions of these pharmaceutically acceptable carriers can be found in The Handbook of Pharmaceutical Excipients published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.

  Methods for formulating pharmaceutical compositions include, for example, Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3, edited by Liberman et al .; Pharmaceutical Dosage: Pent. Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et al .; published in numerous publications such as Marcel Dekker, Inc. publication.

  The compounds of the present invention can be administered in any of the aforementioned compositions and in accordance with established dosage regimes whenever treatment of a disorder mediated by DPP-1 is required.

  The daily dose of the product may vary from 0.1 to 10,000 mg per day for a human adult, or any amount or range therein. For oral administration, the composition is preferably about 0.01, 0.05, 0.1, 0.5, 1.0, 2.5 to adjust the dosage to the treated patient according to symptoms. , 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250, 500, and 1,000 milligrams of the active ingredient. An effective amount of the drug is usually provided at a dosage level of about 0.01 mg / kg body weight to about 100 mg / kg body weight per day, or any amount or range therein. Preferably, this range is from about 0.1 mg / kg body weight to about 50.0 mg / kg body weight per day, or any amount or range therein. More preferably, this range is from about 0.1 mg / kg body weight to about 25.0 mg / kg body weight per day, or any amount or range therein. More preferably, this range is from about 0.1 mg / kg body weight to about 15.0 mg / kg body weight per day, or any amount or range therein. More preferably, this range is from about 0.1 mg / kg body weight to about 10.0 mg / kg body weight per day, or any amount or range therein. More preferably, this range is from about 0.1 mg / kg body weight to about 5.0 mg / kg body weight per day, or any amount or range therein. The compounds may be administered on a regimen of 1 to 4 times per day.

  The optimal dosage to be administered can be readily determined by one skilled in the art and can vary with the particular compound used, the method of administration, the strength of the preparation, the method of administration, and the progression of the disease. In addition, dosage may need to be adjusted depending on factors associated with the particular patient being treated, such as patient age, weight, dietary content, and time of administration.

  One skilled in the art will be able to predict the performance of a test compound to treat or prevent such disorders in both in vivo and in vitro studies using appropriate, known and generally accepted cells and / or animal models. Will recognize. For example, Methot, N .; , Et al. , “In Vivo Inhibition of Serine Protease Processing Requests a High Fractional Inhibition of Cathepsin C”, Molecular Pharmacology, (2008), Vol. 73, no. 6, pp 1857-1865 presents an in vivo assay in rats to measure inhibition of cathepsin C (DPP-1).

  Those skilled in the art will further conduct clinical trials in humans, including first-in-human, dose ranges and efficacy studies, for healthy patients and / or those suffering from the above disorders. It will be appreciated that and can be accomplished according to methods well known in the medical field.

  The following examples are set forth to aid the understanding of the present invention and are not intended to be limiting in any way as it is intended to limit the invention described in the appended claims. Absent.

  In the following examples, some synthesis products are listed as isolated as residues. One skilled in the art will appreciate that the term “residue” is not intended to limit the physical state in which the product is isolated, but may include, for example, solids, oils, foams, gums, syrups, and the like. .

(Example 1)
(S) -N- (3- (1H-indol-2-yl) propyl) -2-aminobutanamide (Compound # 40)

Step A: Pent-4-in-1-amine A 1 L round bottom flask was charged with 2- (pent-4-ynyl) isoindoleine-1,2-dione (25.3 g, 0.119 mol), ethanol. (390 mL) and water (4.4 mL) were added. Hydrazine (7.8 mL, 0.248 mol) was added and the resulting mixture was stirred at room temperature for 24 hours. Water (90 mL) was added and the resulting mixture was acidified to pH 3 using 2N HCl and then stirred at room temperature for 30 minutes. The resulting solid was filtered and the filtrate was concentrated under reduced pressure. Water (90 mL) was added to the resulting residue and the mixture was cooled using an ice / water bath. 10M NaOH solution (100 mL) was added slowly and the resulting mixture was stirred at room temperature for 15 minutes. The resulting mixture was then extracted with dichloromethane (600 mL, 2 times) and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give pent-4-in-1-amine as an oil, Used in the next step without further purification. ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.81 (t, J = 6.8 Hz, 2H), 2.24 to 2.31 (m, 2H), 1.96 (s, 1H), and 1. 62 to 1.71 (m, 2H)

Step B: (S) -N- (pent-4-ynyl) -2- (2,2,2-trifluoroacetamido) butanamide In a 500 mL round bottom flask, (S) -2-aminobutyric acid (5.0 g) was added. 0.048 mol) and dichloromethane (170 mL). The resulting mixture was cooled using an ice / water bath. Trifluoroacetic anhydride (8.8 mL, 0.063 mol) was slowly added and the resulting mixture was stirred at room temperature for 18 hours. The resulting mixture was then concentrated under reduced pressure to give 2- (S)-(2,2,2-trifluoroacetylamino) -butyric acid as an oil that was used without further purification.

To a 500 mL round bottom flask was added 2- (S)-(2,2,2-trifluoroacetylamino) -butyric acid (5.0 g, 0.025 mol), 1-hydroxy-benzotriazole hydrate (4.5 g). , 0.033 mol), N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride (6.4 g, 0.033 mol), 4- (dimethylamino) pyridine (0.02 g, 0.163 mmol), Dimethylformamide (95 mL) was added. To the resulting mixture was then added triethylamine (10.6 mL, 0.076 mol) and pent-4-yne-1-amine (2.7 g, 0.033 mol). The resulting mixture was stirred at room temperature for 22 hours and then concentrated under reduced pressure to give a residue that was flash chromatographed on silica gel (Analogix IF-280, SF 65-400 g column, gradient 90: 10-40: 60 (heptane: EtOAc) to give (S) -N- (pent-4-ynyl) -2- (2,2,2-trifluoroacetamido) butanamide. ¹ H NMR (300 MHz, CDCl ₃ ) δ 4.46 to 4.53 (m, 1H), 3.32 to 3.48 (m, 2H), 2.23 to 2.29 (m, 2H), 2 0.000 (s, 1H), 1.86-1.98 (m, 2H), 1.71-1.83 (m, 2H), and 0.91-0.98 (m, 3H).

Step C: N- [5- (2-aminophenyl) pent-4-ynyl] -2- (S)-(2,2,2-trifluoroacetylamino) butyramide In a 50 mL round bottom flask, add (S) -N- (pent-4-ynyl) -2- (2,2,2-trifluoroacetamido) butanamide (110 mg, 0.42 mmol), 2-iodoaniline (89.0 mg, 0.41 mmol), copper iodide (13.0 mg, 0.068 mmol), palladium tetrakistriphenylphosphine (47 mg, 0.041 mmol), and diethylamine (12.6 mL) were added. The resulting mixture was stirred at room temperature for 4 hours, concentrated under reduced pressure, and the resulting residue was purified by flash silica gel chromatography (Analogix IF-280, SF25-40 g column, gradient 90: 10-10: 90). (Putane: EtOAc) to give N- [5- (2-aminophenyl) pent-4-ynyl] -2- (S)-(2,2,2-trifluoroacetylamino) butyramide. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.21 to 7.24 (m, 1H), 7.07 to 7.12 (m, 1H), 6.64 to 6.71 (m, 1H), 6 .42 to 6.46 (m, 1H), 4.38 to 4.45 (m, 1H), 3.39 to 3.53 (m, 2H), 2.53 (t, J = 6.8 Hz, 2H), 1.67-1.96 (m, 4H), and 0.88-0.93 (m, 3H).

Step D: (S) -N- (3- (1H-indol-2-yl) propyl) -2- (2,2,2-trifluoroacetamido) butanamide In a 50 mL round bottom flask, N- [5- (2-Aminophenyl) pent-4-ynyl] -2- (S)-(2,2,2-trifluoroacetylamino) butyramide (130 mg, 0.37 mmol), dichlorobis (benzonitrile) palladium (II) ( 38.0 mg, 0.099 mmol), and dimethylformamide (4.1 mL) were added and the resulting mixture was heated to 80 ° C. for 22 hours. The resulting mixture is then concentrated under reduced pressure and the resulting residue is purified by flash silica gel chromatography (Analogix IF-280, SF25-40 g column, gradient 90: 10-50: 50 heptane: EtOAc). (S) -N- (3- (1H-indol-2-yl) propyl) -2- (2,2,2-trifluoroacetamido) butanamide was obtained. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.48 to 7.53 (m, 1H), 7.32 (d, J = 7.9 Hz, 1H), 7.04 to 7.15 (m, 2H) 6.23 (s, 1H), 4.32 to 4.39 (m, 1H), 3.31 to 3.38 (m, 2H), 2.71 to 2.75 (m, 2H), 1 .82-1.95 (m, 3H), 1.63-1.77 (m, 1H), and 0.90-0.95 (m, 3H); MS (ES ⁺ ) 356 (M + 1).

Step E: (S) -N- (3- (1H-indol-2-yl) propyl) -2-aminobutanamide In a 20 mL cintillation vial, (S) -N- (3- (1H- Indol-2-yl) propyl) -2- (2,2,2-trifluoroacetamido) butanamide (48.2 mg, 0.136 mmol), tetrahydrofuran (0.68 mL), and methanol (0.18 mL) were added. . 3N sodium hydroxide (0.14 mL, 0.407 mmol) was added and the resulting mixture was stirred at room temperature for 18 hours. The resulting mixture was then diluted with dichloromethane and extracted with 1N HCl. The aqueous layer was neutralized to pH 8 and extracted with dichlormethane. The organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure. The resulting solid was taken up in water and lyophilized to give (S) -N- (3- (1H-indol-2-yl) propyl) -2-aminobutanamide. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.52 (d, J = 7.6 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.01 to 7.13 (m, 2H), 6.22 (s, 1H), 3.30 to 3.49 (m, 3H), 2.72 to 2.77 (m, 2H), 1.83 to 1.96 (m, 3H) , 1.58-1.66 (m, 1H), and 0.98 (t, J = 7.4 Hz, 3H); MS (ES ⁺ ) 260 (M + 1).

(Example 2)
(S) -2-Amino-N- (3- (1-methyl-1H-indol-2-yl) propyl) butanamide (Compound # 41)

Step A: N- [3- (1-Methyl-1H-indol-2-yl) -propyl] -2- (S)-(2,2,2-trifluoro-acetylamino) -butyramide 20 mL scintillation vial (S) -N- (3- (1H-indol-2-yl) propyl) -2- (2,2,2-trifluoroacetamido) butanamide (60 mg, 0.169 mmol), and dimethylformamide (0 .75 mL) was added. Sodium hydride (6.0 mg, 0.25 mmol) was added and the resulting mixture was stirred at room temperature for 15 minutes. Methyl iodide (0.012 mL, 0.193 mmol) was added and the resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was then concentrated under reduced pressure and purified by flash silica gel chromatography (Analogix IF-280, SF25-40 g column, gradient 90: 10-50: 50 heptane: EtOAc) and N- [3- (1-Methyl-1H-indol-2-yl) -propyl] -2- (S)-(2,2,2-trifluoro-acetylamino) -butyramide was obtained. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.52 (d, J = 7.7 Hz, 1H), 7.25 to 7.28 (m, 1H), 7.14 to 7.19 (m, 1H) 7.04 to 7.10 (m, 1H), 6.26 (s, 1H), 4.31 to 4.36 (m, 1H), 3.64 (s, 3H), 3.33 to 3 .46 (m, 2H), 2.75 to 2.82 (m, 2H), 1.80 to 2.09 (m, 3H), 1.59 to 1.71 (m, 1H), and 0. 87-0.92 (m, 3H); MS (ES ^<+> ) 370 (M + 1).

Step B: (S) -2-Amino-N- (3- (1-methyl-1H-indol-2-yl) propyl) butanamide In a 20 mL scintillation vial, N- (3- (1-methyl-1H— Indol-2-yl) propyl) -2- (S)-(2,2,2-trifluoro-acetylamino) butanamide (57.0 mg, 0.154 mmol), tetrahydrofuran (0.77 mL), and methanol (0 20 mL). 3N sodium hydroxide (0.15 mL, 0.450 mmol) was added and the resulting mixture was stirred at room temperature for 18 hours. The resulting mixture was then diluted with dichloromethane and extracted with 1N HCl. The aqueous layer was neutralized to pH 8 and extracted with dichlormethane. The organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure. The resulting solid was taken up in water and lyophilized to give (S) -2-amino-N- (3- (1-methyl-1H-indol-2-yl) propyl) butanamide. ¹ H NMR (300 MHz, CD ₃ OD) δ 7.42 (d, J = 7.7 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.05 to 7.11 (m , 1H), 6.94 to 7.02 (m, 1H), 6.23 (s, 1H), 3.60 to 3.75 (m, 4H), 3.31 to 3.46 (m, 2H) ) 2.69-2.86 (m, 2H), 1.91-2.03 (m, 2H), 1.71-1.89 (m, 2H), and 1.02 (t, J = 7.4 Hz, 3H); MS (ES ⁺ ) 274 (M + 1).

Representative compounds of the present invention listed in Table 5 below, along with corresponding measured MS (ES ⁺ ) (M + 1) molecular ion mass numbers, were prepared according to the procedures described in Examples 1 and 2 above. The same preparation was made by selecting and using appropriately replaced reagents.

(Example 3)
2- (S) -Amino-N- [3- (1H-indol-3-yl) -propyl] -butyramide (Compound # 44)

Step A: (S) -tert-Butyl 1- (allylamino) -1-oxobutan-2-ylcarbamate To a 500 mL round bottom flask was added (S) -2- (tert-butoxycarbonylamino) butanoic acid (5.0 g). , 0.025 mol), 1-hydroxy-benzotriazole hydrate (3.4 g, 0.025 mol), N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride (7.2 g, 0.038 mol) ), And dichloromethane (125 mL). Triethylamine (7.6 mL, 0.055 mol) and allylamine (1.9 g, 0.025 mol) were added and the resulting mixture was stirred at room temperature for 22 hours. The resulting mixture was then diluted with dichlormethane (300 mL) and washed once with 1N HCl (200 mL), once with 1N NaOH (200 mL), and once with water (200 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give (S) -tert-butyl-1- (allylamino) -1-oxobutan-2-ylcarbamate. ¹ H NMR (300 MHz, CDCl ₃ ) δ 5.77-5.88 (m, 1H), 5.15-5.23 (m, 2H), 4.03-4.19 (m, 1H), 3 .88 to 3.92 (m, 2H), 1.82 to 1.94 (m, 1H), 1.60 to 1.72 (m, 1H), 1.45 (s, 9H), and 0. 96 (t, J = 7.4 Hz, 3H).

Step B: (S, E) -tert-butyl-3- (3- (2- (tert-butoxycarbonylamino) butanamide) prop-1-enyl) -1H-indole-1-carboxylate in a 50 mL sealed tube , (S) -tert-butyl-1- (allylamino) -1-oxobutan-2-ylcarbamate (500 mg, 2.07 mmol), 3-bromo-indole-1-carboxylic acid tert-butyl ester (620 mg, 2. 09 mmol), palladium (II) acetate (59 mg, 0.263 mmol), tri-o-tolylphosphine (180 mg, 0.591), acetonitrile (10 mL), and triethylamine (0.6 mL, 4.30 mmol). The tube was flushed with argon, sealed and heated at 90 ° C. for 24 hours. The resulting mixture was concentrated under reduced pressure and the resulting residue was purified by flash silica gel chromatography (Analogix IF-280, SF 65-150 g column, gradient 90: 10-50: 50 heptane: EtOAc). , (S, E) -tert-butyl 3- (3- (2- (tert-butoxycarbonylamino) butanamide) prop-1-enyl) -1H-indole-1-carboxylate was obtained. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.58 (s, 1H), 7.23 to 7.36 (m, 4H), 6.60 to 6.66 (m, 1H), 6.20 to 6 .51 (m, 1H), 4.05 to 4.11 (m, 1H), 3.86 to 3.91 (m, 2H), 1.83 to 1.93 (m, 1H), 1.59 ~ 1.72 (m, 1H), 1.44 (s, 18H), and 0.95 (t, J = 7.4 Hz, 3H).

Step C: 3- [3- (2- (2- (S) -tert-butoxycarbonylamino-butyrylamino) -propyl] -indole-1-carboxylic acid tert-butyl ester In a 250 mL Parr hydrogenation vessel, add (S, E) -Tert-butyl 3- (3- (2- (tert-butoxycarbonylamino) butanamide) prop-1-enyl) -1H-indole-1-carboxylate (280 mg, 0.42 mmol), 10% palladium-carbon ( 34 mg) and ethanol (6.0 mL). The vessel was evacuated and filled with hydrogen. This was repeated two more times. The vessel was then filled with 344.7 kPa (50 psi) of hydrogen. After 24 hours, the resulting solution was filtered through celite, the filtrate was concentrated under reduced pressure, and 3- [3- (2- (S) -tert-butoxycarbonylamino-butyrylamino) -propyl] -indole- 1-carboxylic acid tert-butyl ester was obtained. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.21 to 7.24 (m, 1H), 7.07 to 7.12 (m, 1H), 6.64 to 6.71 (m, 1H), 6 .42 to 6.46 (m, 1H), 4.38 to 4.45 (m, 1H), 3.39 to 3.53 (m, 2H), 2.53 (t, J = 6.8 Hz, 2H), 1.67-1.96 (m, 4H), and 0.88-0.93 (m, 3H).

Step D: 2- (S) -Amino-N- [3- (1H-indol-3-yl) -propyl] -butyramide In a 20 mL scintillation vial, 3- [3- (2- (S) -tert- Butoxycarbonylamino-butyrylamino) -propyl] -indole-1-carboxylic acid tert-butyl ester (280 mg, 0.61 mmol), dichloromethane (3.6 mL), and 1M hydrochloric acid in diethyl ether (3.0 mL) were added. . The resulting mixture was stirred at room temperature for 4 hours, then concentrated under reduced pressure, the residue was placed under high vacuum overnight and 2- (S) -amino-N- [3- (1H-indole-3- Yl) -propyl] -butyramide was obtained. ¹ H NMR (300 MHz, CD ₃ OD) δ 7.51 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 6.95 to 7.09 (m , 3H), 3.11 to 3.39 (m, 3H), 2.77 to 2.82 (m, 2H), 1.78 to 2.01 (m, 4H), and 0.94 (t, J = 7.4 Hz, 3H); MS (ES ⁺ ) 260 (M + 1).

Compound # 43 was similarly prepared according to the procedure described in Example 3 above, and the measured MS (ES ⁺ ) was 277 (M + 1).

Example 4
(S) -2- (3- (2- (tert-Butoxycarbonylamino) butanamido) propyl) -1H-indole-5-carboxylic acid (Compound # 47)

Step A: (1-Pent-4-ynylcarbamoyl-propyl)-(S) -carbamic acid tert-butyl ester Into a 500 mL round bottom flask was added (S) -2- (tert-butoxycarbonylamino) butanoic acid (5 0.0 g, 0.025 mol), 1-hydroxybenzotriazole hydrate (4.5 g, 0.033 mol), N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride (6.4 g, 0.03 mol). 033 mol), 4- (dimethylamino) pyridine (0.02 g, 0.163 mmol), and dimethylformamide (95 mL) were added. Triethylamine (10.6 mL, 0.076 mol) and pent-4-yne-1-amine (2.7 g, 0.033 mol) were added and the resulting mixture was stirred at room temperature for 22 hours. The resulting mixture is concentrated under reduced pressure and the residue is purified by flash silica gel chromatography (Analogix IF-280, SF 65-400 g column, gradient 90: 10-40: 60 heptane: EtOAc), (1 -Pent-4-ynylcarbamoyl-propyl)-(S) -carbamic acid tert-butyl ester was obtained. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.93 to 4.00 (m, 1H), 3.36 to 3.42 (m, 2H), 2.22 to 2.28 (m, 2H), 2 0.00 (s, 1H), 1.83 to 1.92 (m, 1H), 1.70 to 1.80 (m, 2H), 1.57 to 1.67 (m, 1H), 1.45 (S, 9H), and 0.94 (t, J = 7.4 Hz, 3H).

Step B: 4-amino-3- [5- (2- (S) -tert-butoxycarbonylamino-butyrylamino) -pent-1-ynyl] -benzoic acid methyl ester In a 50 mL round bottom flask, add (1-pento -4-ynylcarbamoyl-propyl)-(S) -carbamic acid tert-butyl ester (2.24 g, 8.36 mmol), methyl 4-amino-3-iodobenzoic acid (2.38 g, 8.59 mmol), iodo Copper chloride (0.21 g, 1.10 mmol), palladium tetrakistriphenylphosphine (1.12 g, 0.97 mmol), and diethylamine (300 mL) were added. The resulting mixture was stirred at room temperature for 4 hours and then concentrated under reduced pressure, and the resulting residue was purified by flash silica gel chromatography (Analogix IF-280, SF 40-400 g column, gradient 90: 10-10: 90). Purification by heptane: EtOAc) gave 4-amino-3- [5- (2- (S) -tert-butoxycarbonylamino-butyrylamino) -pent-1-ynyl] -benzoic acid methyl ester. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.94 (s, 1H), 7.76 (d, J = 6.5 Hz, 1H), 6.64 (d, J = 8.5 Hz, 1H), 3 .91 to 4.09 (m, 1H), 3.85 (s, 3H), 3.47 to 3.52 (m, 2H), 2.52 (t, J = 6.8 Hz, 2H), 1 .75 to 1.92 (m, 3H), 1.60 to 1.69 (m, 1H), 1.44 (s, 9H), and 0.94 (t, J = 7.4 Hz, 3H).

Step C: (S) -Methyl 2- (3- (2- (tert-butoxycarbonylamino) butanamido) propyl) -1H-indole-5-carboxylate Into a 250 mL round bottom flask was added 4-amino-3- [ 5- (2- (S) -tert-butoxycarbonylamino-butyrylamino) -pent-1-ynyl] -benzoic acid methyl ester (2.51 g, 6.02 mmol), dichlorobis (benzonitrile) palladium (II) (490 mg , 1.28 mmol), and dimethylformamide (67 mL) and the resulting mixture was heated to 80 ° C. for 24 hours. The resulting mixture was then concentrated under reduced pressure and the residue was purified by flash silica gel chromatography (Analogix IF-280, SF25-40 g column, heptane: EtOAc gradient 90: 10-30: 70) (S ) -Methyl 2- (3- (2- (tert-butoxycarbonylamino) butanamido) propyl) -1H-indole-5-carboxylate was obtained. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.29 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 6 .31 (s, 1H), 3.95 to 4.02 (m, 1H), 3.92 (s, 3H), 3.33 to 3.53 (m, 2H), 2.74 to 2.87 (M, 2H), 1.81-1.99 (m, 3H), 1.60-1.75 (m, 1H), 1.45 (s, 9H), and 0.99 (t, J = 7.4 Hz, 3H); MS (ES ⁺ ) 418 (M + 1).

Step D: (S) -2- (3- (2- (tert-butoxycarbonylamino) butanamido) propyl) -1H-indole-5-carboxylic acid In a 200 mL round bottom flask, add (S) -methyl 2- ( 3- (2- (tert-Butoxycarbonylamino) butanamido) propyl) -1H-indole-5-carboxylate (1.67 g, 4.00 mmol), tetrahydrofuran (20 mL), and methanol (5.3 mL) were added. . 3N sodium hydroxide (4.0 mL, 12.0 mmol) was added and the resulting mixture was stirred and heated to 50 ° C. for 8 hours. The resulting mixture was then cooled to room temperature and acidified with 1N hydrochloric acid. The resulting mixture was extracted twice with ethyl acetate (400 mL). The organic layer was dried over MgSO ₄ , filtered, concentrated under reduced pressure and (S) -2- (3- (2- (tert-butoxycarbonylamino) butanamido) propyl) -1H-indole-5-carboxylic acid. Got. ¹ H NMR (300 MHz, CD ₃ OD) δ 8.20 (s, 1H), 7.75 (d, J = 7.0 Hz, 1H), 7.32 (d, J = 8.6 Hz, 1H), 6.31 (s, 1H), 3.94 to 4.10 (m, 1H), 3.22 to 3.34 (m, 2H), 2.80 to 2.85 (m, 2H), 1. 61-2.08 (m, 4H), 1.46 (s, 9H), and 0.93-1.03 (m, 3H); MS (ES ⁺ ) 403 (M + 1).

(Example 5)
(S) -2- (3- (2-Aminobutanamido) propyl) -N- (3,4-dimethoxyphenyl) -1H-indole-5-carboxamide (Compound # 50)

Step A: (1- {3- [5- (3,4-Dimethoxy-phenylcarbamoyl) -1H-indol-2-yl] -propylcarbamoyl} -propyl)-(S) -carbamic acid tert-butyl ester 50 mL In a round bottom flask, (S) -2- (3- (2- (tert-butoxycarbonylamino) butanamido) propyl) -1H-indole-5-carboxylic acid (740 mg, 1.84 mmol), bis (2- Oxo-3-oxazolidinyl) phosphinic chloride (530 mg, 2.08 mmol) and dichloromethane (10.6 mL) were added. Triethylamine (0.8 mL, 5.74 mmol) was added and the resulting mixture was stirred at room temperature for 15 minutes. 3,4-Dimethoxyaniline (290 mg, 1.89 mmol) was added and the resulting mixture was stirred at room temperature for 23 hours. The resulting mixture was then concentrated under reduced pressure and the residue was purified by flash silica gel chromatography (Analogix IF-280, SF 40-115 g column, gradient 100: 0-94: 6 CH ₂ Cl ₂ : MeOH), (1- {3- [5- (3,4-Dimethoxy-phenylcarbamoyl) -1H-indol-2-yl] -propylcarbamoyl} -propyl)-(S) -carbamic acid tert-butyl ester was obtained. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.85 to 7.89 (m, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.43 (s, 1H), 7.20 ˜7.30 (m, 2H), 6.83 (d, J = 8.8 Hz, 1H), 6.23 (s, 1H), 4.33 to 4.40 (m, 1H), 3.76 (S, 3H), 3.73 (s, 3H), 3.26 to 3.40 (m, 2H), 2.56 to 2.68 (m, 2H), 1.73 to 1.84 (m) , 3H), 1.52-1.67 (m, 1H), 1.36 (s, 9H), and 0.90 (t, J = 7.2 Hz, 3H); MS (ES ⁺ ) 539 (M + 1) ).

Step B: (S) -2- (3- (2-Aminobutanamido) propyl) -N- (3,4-dimethoxyphenyl) -1H-indole-5-carboxamide In a 50 mL round bottom flask, add (1- {3- [5- (3,4-Dimethoxy-phenylcarbamoyl) -1H-indol-2-yl] -propylcarbamoyl} -propyl)-(S) -carbamic acid tert-butyl ester (810 mg, 1.51 mmol) And dichloromethane (7.5 mL) was added. 1M hydrochloric acid in diethyl ether (7.5 mL) was added and the resulting mixture was stirred at room temperature for 40 minutes. The resulting mixture was then concentrated under reduced pressure and the residue was triturated with diethyl ether and placed under high vacuum to provide (S) -2- (3- (2-aminobutanamido) propyl) -N- ( 3,4-Dimethoxyphenyl) -1H-indole-5-carboxamide was obtained. ¹ H NMR (300 MHz, DMSO) δ 7.85 to 7.89 (m, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.43 (s, 1H), 7.20 to 7.30 (m, 2H), 6.83 (d, J = 8.8 Hz, 1H), 6.23 (s, 1H), 3.67 (s, 3H), 3.65 (s, 3H) 3.59 to 3.63 (m, 1H), 3.04 to 3.37 (m, 2H), 2.64 to 2.79 (m, 2H), 1.80 to 1.96 (m, 2H), 1.62-1.77 (m, 2H), and 0.97 (t, J = 7.2 Hz, 3H); MS (ES ⁺ ) 439 (M + 1); C ₂₄ H ₃₀ N ₄ O ₄ Calculated for 1.1 HCl.0.7 H ₂ O: C, 58.68; H, 6.67; N, 11.41; Cl, 7.94; H ₂ O, 2.57. Found: C, 58.88; H, 6.98 ; N, 11.73; Cl, 7.50; H 2 O, 2.32.

The representative compounds of the present invention listed in Table 6 below along with the corresponding measured MS (ES ⁺ ) (M + 1) molecular ion mass numbers can be suitably replaced according to the procedures described in Examples 4 and 5 above. It was prepared similarly by selecting and using reagents.

(Example 6)
(S) -2-Amino-1- (4- (5- (3,4-dimethoxyphenyl) -1H-indol-2-yl) piperidin-1-yl) -3- (thiophen-2-yl) propane -1-one (compound # 2)

Step A: 4- (2-Amino-5-bromo-phenylethynyl) -piperidine-1-carboxylic acid tert-butyl ester In a 50 mL round bottom flask, tert-butyl 4-ethynylpiperidine-1-carboxylate (3. 51 g, 16.8 mmol), methyl 4-amino-3-iodobenzoic acid (5.0 g, 16.8 mmol), copper iodide (0.35 g, 1.85 mmol), palladium tetrakistriphenylphosphine (1.94 g, 1.68 mmol) and diethylamine (560 mL) were added, and the resulting mixture was stirred at room temperature for 24 hours. The resulting mixture was then concentrated under reduced pressure and the residue was purified by flash silica gel chromatography (Analogix IF-280, SF 40-400 g column, gradient 90:10 to 70:30 heptane: EtOAc). -(2-Amino-5-bromo-phenylethynyl) -piperidine-1-carboxylic acid tert-butyl ester was obtained. MS (ES ^<+> ) 380 (M + l).

Step B: tert-Butyl 4- (5-bromo-1H-indol-2-yl) piperidine-1-carboxylate In a 250 mL round bottom flask, 4- (2-amino-5-bromo-phenylethynyl) -piperidine. -1-carboxylic acid tert-butyl ester (5.90 g, 15.6 mmol), dichlorobis (benzonitrile) palladium (II) (1.20 g, 3.13 mmol), and dimethylformamide (175 mL) were obtained and obtained. The mixture was heated to 80 ° C. for 24 hours. The resulting mixture was then concentrated under reduced pressure and the residue was purified by flash silica gel chromatography (Analogix IF-280, SF25-40 g column, gradient 90: 10-80: 20 heptane: EtOAc) and tert -Butyl 4- (5-bromo-1H-indol-2-yl) piperidine-1-carboxylate was obtained. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.66 (s, 1H), 7.16 to 7.23 (m, 2H), 6.20 (s, 1H), 2.84 to 3.02 (m , 5H), 1.97 to 2.04 (m, 2H), 1.61 to 1.74 (m, 2H), and 1.48 (s, 9H); MS (ES ⁺ ) 380 (M + 1).

Step C: 4- [5- (3,4-Dimethoxy-phenyl) -1H-indol-2-yl] -piperidine-1-carboxylic acid tert-butyl ester In a 100 mL sealed tube, tert-butyl 4- (5 -Bromo-1H-indol-2-yl) piperidine-1-carboxylate (1.04 g, 2.74 mmol), 3,4-dimethoxyphenylboronic acid (0.58 g, 3.19 mmol), 1,1′- Bis (di-t-butylphosphino) ferrocene palladium dichloride (0.11 g, 0.169 mmol), 10% aqueous sodium carbonate solution (6.1 mL), and 1,4-dioxane (13. 2 mL). The vessel was then flushed with argon and sealed. The resulting mixture was stirred at 100 ° C. for 24 hours, then the mixture was diluted with dichloromethane (300 mL) and washed with water (100 mL). The organic layer was dried over MgSO ₄ , filtered, concentrated under reduced pressure and 4- [5- (3,4-dimethoxy-phenyl) (5- (3,4-cimethoxy-phenyl))-1H-indole. -2-yl] -piperidine-1-carboxylic acid tert-butyl ester was obtained. ¹ H NMR (300 MHz, CD ₃ OD) δ 7.71 (s, 1H), 7.33-7.38 (m, 2H), 7.15-7.24 (m, 2H), 6.95 ( d, J = 8.0 Hz, 1H), 6.31 (s, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 2.85 to 2.93 (m, 5H) 2.02 to 2.11 (m, 2H), 1.65 to 1.77 (m, 2H), and 1.49 (s, 9H); MS (ES ⁺ ) 437 (M + 1).

Step D: 5- (3,4-Dimethoxyphenyl) -2- (piperidin-4-yl) -1H-indole Into a 50 mL round bottom flask was added 4- [5- (3,4-dimethoxy-phenyl) -1H. -Indol-2-yl] -piperidine-1-carboxylic acid tert-butyl ester (500 mg, 1.15 mmol), dichloromethane (5.8 mL), and 1M hydrochloric acid in diethyl ether (5.8 mL) were obtained. The mixture was stirred for 2 hours. The resulting mixture is then concentrated under reduced pressure and the residue is triturated with diethyl ether and then placed under high vacuum to give 5- (3,4-dimethoxyphenyl) -2- (piperidin-4-yl) -1H-indole was obtained. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.69 (s, 1H), 7.29-7.37 (m, 2H), 7.09-7.22 (m, 2H), 6.99 (D, J = 8.2 Hz, 1H), 6.22 (s, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 3.67 to 3.74 (m, 1H) ), 3.02 to 3.15 (m, 4H), 2.50 to 2.61 (m, 2H), and 1.81 to 2.01 (m, 2H); MS (ES ⁺ ) 337 (M + 1) ).

Step E: (2- {4- [5- (3,4-Dimethoxy-phenyl) -1H-indol-2-yl] -piperidin-1-yl} -2-oxo-1-thiophen-2-ylmethyl- Ethyl)-(S) -carbamic acid tert-butyl ester A 50 mL round bottom flask was charged with (S) -2- (tert-butoxycarbonylamino) -3- (thiophen-2-yl) propanoic acid (42.1 mg, 0.155 mmol), 1-hydroxybenzotriazole hydrate (27.3 mg, 0.201 mmol), N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride (38.6 mg, 0.201 mmol), 4- (Dimethylamino) pyridine (1.0 mg, 0.008 mmol) and dimethylformamide (2.0 mL) were added. Add triethylamine (0.07 mL, 0.502 mmol) and 5- (3,4-dimethoxyphenyl) -2- (piperidin-4-yl) -1H-indole (77.0 mg, 0.207 mmol) to obtain The mixture was stirred at room temperature for 22 hours. The resulting mixture was then concentrated under reduced pressure and the residue was purified by flash silica gel chromatography (ISCO, SF 25-40 g column, gradient 90: 10-75: 25 heptane: EtOAc) and (2- {4 -[5- (3,4-Dimethoxy-phenyl) -1H-indol-2-yl] -piperidin-1-yl} -2-oxo-1-thiophen-2-ylmethyl-ethyl)-(S) -carbamine The acid tert-butyl ester was obtained. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.7 (s, 1H), 7.4 (m, 2H), 7.2 (m, 3H), 7.0 (m, 3H), 6.99 ( d, J = 8.2 Hz, 1H), 6.22 (s, 1H), 5.4 (m, 1H), 4.6 to 4.9 (m, 2H), 4.0 (s, 3H) 3.9 (s, 3H), 3.1-3.3 (m, 4H), 2.78 (m, 1H), 1.4-1.6 (m, 4H); MS (ES ⁺ ) 590 (M + 1).

Step F: (S) -2-Amino-1- (4- (5- (3,4-dimethoxyphenyl) -1H-indol-2-yl) piperidin-1-yl) -3- (thiophen-2- Yl) propan-1-one In a 50 mL round bottom flask, (1- {3- [5- (3,4-dimethoxy-phenylcarbamoyl) -1H-indol-2-yl] -propylcarbamoyl} -propyl)- (S) -Carbamic acid tert-butyl ester (69.0 mg, 0.117 mmol) and dichloromethane (1 mL) were added. 1M hydrochloric acid in diethyl ether (3 mL) was added and the resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was then concentrated under reduced pressure and the residue (oil) was filtered using a Gilson HPLC (10u, 100Å C18, column length 250 × 50 mm, gradient 80:20 to 0: 100 H with a reverse phase Kromasil column ₂ O: MeCN) was purified on. The resulting solid was taken up in dichloromethane and treated with 1M hydrochloric acid in diethyl ether. The resulting mixture was concentrated under reduced pressure. This procedure was repeated two more times to give (S) -2-amino-1- (4- (5- (3,4-dimethoxyphenyl) -1H-indol-2-yl) piperidin-1-yl) -3- (Thiophen-2-yl) propan-1-one was obtained. ¹ H NMR (300 MHz, DMSO) δ 7.73 (m, 1H), 7.35 to 7.78 (m, 3H), 7.43 (s, 1H), 7.12 to 7.30 (m, 2H), 6.83 to 7.01 (m, 3H), 6.15 (s, 1H), 4.42 to 4.53 (m, 2H), 3.95 (m, 1H), 3.81 (S, 3H), 3.62 (s, 3H), 3.11 to 3.25 (m, 4H), 3.01 (m, 1H), 2.41 (m, 2H), 1.81 ( m, 2H); MS (ES ⁺ ) 490 (M + 1).

The representative compounds of the present invention listed in Table 7 below along with the corresponding measured MS (ES ⁺ ) (M + 1) molecular ion mass numbers are replaced with reagents that can be appropriately replaced according to the procedure described in Example 6 above. It was prepared similarly by selecting and using.

(Example 7)
(S) -2- (3- (2-Amino-3- (thiazol-2-yl) propanamido) propyl) -N- (3,4-dimethoxyphenyl) -1H-indole-5-carboxamide (Compound # 117) )

Step A: 2- (S) -tert-butoxycarbonylamino-3-thiocarbamoyl-propionic acid benzyl ester To a 1 L round bottom flask, add (S) -benzyl 4-amino-2- (tert-butoxycarbonylamino)- 4-Oxobutanoic acid (10.0 g, 31.0 mmol), Lawesson's reagent (6.58 g, 16.3 mmol), and tetrahydrofuran (155 mL) were added. Hydrazine (7.8 mL, 0.248 mol) was added and the resulting mixture was stirred at room temperature for 72 hours. The resulting mixture was then concentrated under reduced pressure and the residue was purified by flash silica gel chromatography (Analogix IF-280, SF 40-400 g column, gradient 90: 10-60: 40 heptane: EtOAc) and-( S) -tert-Butoxycarbonylamino-3-thiocarbamoyl-propionic acid benzyl ester was obtained. MS (ES ^<+> ) 339 (M + 1).

Step B: 2- (S) -tert-Butoxycarbonylamino-3-thiazol-2-yl-propionic acid benzyl ester In a 250 mL round bottom flask, add 2- (S) -tert-butoxycarbonylamino-3-thiocarbamoyl- Propionic acid benzyl ester (1.0 g, 2.96 mmol), dimethoxyethane (66 mL), and diethyl acetal bromoacetate (2.4 mL, 15.5 mmol) were added. The flask containing the resulting mixture was fitted with a reflux condenser and the mixture was refluxed for 3 hours. The resulting mixture is then concentrated under reduced pressure and the residue is purified by flash silica gel chromatography (Analogix IF-280, SF 65-400 g column, gradient 100: 0-90: 10 CH ₂ Cl ₂ : MeOH). 2- (S) -tert-butoxycarbonylamino-3-thiazol-2-yl-propionic acid benzyl ester was obtained. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.67 (d, J = 3.3 Hz, 1H), 7.29-7.44 (m, 5H), 7.20 (d, J = 3.3 Hz, 1H), 5.15 (s, 2H), 5.75 (t, J = 5.5 Hz, 1H), 73.15 (d, J = 7.4 Hz, 1H), and 1.44 (s, 9H) ); MS (ES ⁺ ) 363 (M + 1).

Step C: (S) -2- (tert-Butoxycarbonylamino) -3- (thiazol-2-yl) propanoic acid In a 100 mL round bottom flask, add 2- (S) -tert-butoxycarbonylamino-3-thiazole 2 -Yl-propionic acid benzyl ester (370 mg, 1.02 mmol), tetrahydrofuran (9.0 mL), water (0.9 mL), and lithium hydroxide (48 mg, 1.14 mmol) were charged and the resulting mixture was stirred at room temperature. Stir for 6 hours. The resulting mixture was then neutralized with 10% citric acid, extracted with ethyl acetate (100 mL), and extracted with dichlormethane (100 mL). The organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure to give (S) -2- (tert-butoxycarbonylamino) -3- (thiazol-2-yl) propanoic acid. MS (ES ^<+> ) 273 (M + 1).

Step D: 4-Amino-N- (3,4-dimethoxyphenyl) -3-iodobenzamide In a 500 mL round bottom flask, methyl 4-amino-3-iodobenzoic acid (10.0 g, 36.1 mmol), methanol (270 mL), water (30 mL), and lithium hydroxide (1.82 g, 43.3 mmol) were added. The vessel was flushed with nitrogen and attached to a reflux condenser and the mixture was heated to a gentle reflux for 20 hours. The resulting mixture was then cooled to room temperature, acidified with 2N hydrochloric acid and then concentrated under reduced pressure. The resulting solid (9.5 g, 36.7 mmol) was placed in a 500 mL round bottom flask and dichloromethane (180 mL) was added. Bis (2-oxo-3-oxazolidinyl) phosphinic chloride (10.0 g, 39.5 mmol) and triethylamine (11.1 mL, 79.2 mmol) were added. 3,4-Dimethoxyaniline (11.1 g, 72.1 mmol) was then added and the resulting mixture was stirred at room temperature for 24 hours. The resulting mixture was then diluted with ethyl acetate and washed with 1N NaOH. The organic layer was dried over MgSO ₄ , filtered and then concentrated under reduced pressure to give 4-amino-N- (3,4-dimethoxyphenyl) -3-iodobenzamide. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.23 (s, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.42 (s, 1H), 7.30 (d, J = 8.6 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 6.77 (d, J = 8.5 Hz, 1H), 3.74 (s, 3H), and 3. 72 (s, 3H).

Step E: Pent-4-ynyl-carbamic acid tert-butyl ester A 1 L round bottom flask was charged with pent-4-yn-1-amine (10.0 g, 0.120 mol), dichloromethane (600 mL), and triethylamine (33 .6 mL, 0.241 mol) was added. The resulting mixture was cooled with an ice / water bath. Additional di-tert-butyl dicarbonate (38.4 g, 0.176 mol) was added in three portions and the resulting mixture was stirred at room temperature for 72 hours. The resulting mixture is then concentrated under reduced pressure and the residue is purified by flash silica gel chromatography (Analogix IF-280, SF 65-400 g column, gradient 90: 10-80: 20 heptane: EtOAc) and pent. -4-Inyl-carbamic acid tert-butyl ester was obtained. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.20 to 3.26 (m, 2H), 2.21 to 2.27 (m, 2H), 1.97 (s, 1H), 1.67 to 1 .82 (m, 2H) and 1.44 (s, 9H).

Step F: {5- [2-Amino-5- (3,4-dimethoxy-phenylcarbamoyl) -phenyl] -pent-4-ynyl} -carbamic acid tert-butyl ester Into a 500 mL round bottom flask was added pent-4. -Inyl-carbamic acid tert-butyl ester (1.35 g, 7.37 mmol), 4-amino-N- (3,4-dimethoxyphenyl) -3-iodobenzamide (1.35 g, 6.98 mmol), iodinated Copper (0.16 g, 0.814 mmol), palladium tetrakistriphenylphosphine (0.81 g, 0.701 mmol), and diethylamine (230 mL) were added and the resulting mixture was stirred at room temperature for 24 hours. The resulting mixture was then concentrated under reduced pressure and the residue was purified by flash silica gel chromatography (Analogix IF-280, SF 40-400 g column, gradient 90: 10-10: 90 heptane: EtOAc), {5 -[2-Amino-5- (3,4-dimethoxy-phenylcarbamoyl) -phenyl] -pent-4-ynyl} -carbamic acid tert-butyl ester was obtained. MS (ES ^<+> ) 454 (M + 1).

Step G: tert-Butyl 3- (5- (3,4-dimethoxyphenylcarbamoyl) -1H-indol-2-yl) propylcarbamate In a 500 mL round bottom flask, add {5- [2-amino-5- (3 , 4-Dimethoxy-phenylcarbamoyl) -phenyl] -pent-4-ynyl} -carbamic acid tert-butyl ester (3.0 g, 6.62 mmol), dichlorobis (benzonitrile) palladium (II) (0.514 g, 1 .34 mmol), and dimethylformamide (80 mL) were added and the resulting mixture was heated to 80 ° C. for 24 hours. The resulting mixture was then concentrated under reduced pressure and the residue was subjected to flash silica gel chromatography (Analogix IF-280, SF25-40 g column, gradient 100: 0 to 90:10 CH ₂ Cl ₂ : MeOH) and tert. -Butyl 3- (5- (3,4-dimethoxyphenylcarbamoyl) -1H-indol-2-yl) propylcarbamate was obtained. MS (ES ⁺ ) 454 (M + 1); HPLC: Kromasil C18 column (50 × 2 mm; 3.5 μ), (MeCN + 0.16% TFA) gradient 10-90 in (water + 0.2% TFA) over 4 minutes. %, T _R = 3.78 min.

Step H: 2- (3-Amino-propyl) -1H-indole-5-carboxylic acid (3,4-dimethoxy-phenyl) -amide A 250 mL round bottom flask was charged with tert-butyl 3- (5- (3, 4-Dimethoxyphenylcarbamoyl) -1H-indol-2-yl) propylcarbamate (3.0 g, 6.62 mmol), dichloromethane (33 mL), and 1M hydrochloric acid in diethyl ether (33 mL) were added and the resulting mixture was Stir for 2 hours. The resulting mixture was then concentrated under reduced pressure and the residue was triturated with diethyl ether and placed under high vacuum to give 2- (3-amino-propyl) -1H-indole-5-carboxylic acid (3,4). -Dimethoxy-phenyl) -amide was obtained. MS (ES ⁺ ) 354 (M + 1); HPLC: Kromasil C18 column (50 × 2 mm; 3.5 μ), (MeCN + 0.16% TFA) gradient 10-90% in (water + 0.2% TFA) over 4 minutes , t _R = 2.46 min.

Step I: (1- {3- [5- (3,4-Dimethoxy-phenylcarbamoyl) -1H-indol-2-yl] -propylcarbamoyl} -2-thiazol-2-yl-ethyl)-(S) -Carbamic acid tert-butyl ester A 50 mL round bottom flask was charged with (S) -2- (tert-butoxycarbonylamino) -3- (thiazol-2-yl) propanoic acid (110 mg, 0.404 mmol), 1-hydroxybenzo Triazole hydrate (74.8 mg, 0.553 mmol), N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride (198 mg, 1.03 mmol), and dichlormethane (2.2 mL). I put it in. To the resulting mixture was then added triethylamine (0.22 mL, 1.58 mmol) and 2- (3-amino-propyl) -1H-indole-5-carboxylic acid (3,4-dimethoxy-phenyl) -amide (220 mg, 0.564 mmol) was added. The resulting mixture was stirred at room temperature for 24 hours, then concentrated under reduced pressure and the residue was filtered using a Gilson HPLC (10μ, 100Å C18, column length 250 × 50 mm, gradient 70: 30-0 with a reverse phase Kromasil column. : 100 H ₂ O: MeCN) and (1- {3- [5- (3,4-dimethoxy-phenylcarbamoyl) -1H-indol-2-yl] -propylcarbamoyl} -2 -Thiazol-2-yl-ethyl)-(S) -carbamic acid tert-butyl ester was obtained. MS (ES ⁺ ) 608 (M + 1); HPLC: Kromasil C18 column (50 × 2 mm; 3.5 μ), (MeCN + 0.16% TFA) gradient 10-90 in (water + 0.2% TFA) over 4 minutes. %, T _R = 3.47 min.

Step J: (S) -2- (3- (2-amino-3- (thiazol-2-yl) propanamido) propyl) -N- (3,4-dimethoxyphenyl) -1H-indole-5-carboxamide 50 mL In a round bottom flask, (1- {3- [5- (3,4-dimethoxy-phenylcarbamoyl) -1H-indol-2-yl] -propylcarbamoyl} -2-thiazol-2-yl-ethyl) -(S) -Carbamic acid tert-butyl ester (213.3 mg, 0.351 mmol) and dichloromethane (1.8 mL) were added. 1M hydrochloric acid in diethyl ether (1.8 mL) was added and the resulting mixture was stirred at room temperature for 1.5 hours. The resulting mixture was then concentrated under reduced pressure to give (S) -2- (3- (2-amino-3- (thiazol-2-yl) propanamido) propyl) -N- (3,4-dimethoxyphenyl). -1H-indole-5-carboxamide was obtained. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.13 (s, 1H), 7.75-7.87 (m, 1H), 7.61-7.70 (m, 2H), 7.50 7.55 (m, 1H), 7.35-7.45 (m, 2H), 6.91 (d, J = 8.8 Hz, 1H), 6.29 (s, 1H), 3.76. (S, 3H), 3.74 (s, 3H), 3.60 to 3.71 (m, 1H), 3.53 (d, J = 6.5 Hz, 2H), 3.01 to 3.31 (M, 2H), 2.69-2.82 (m, 2H), and 1.76-1.91 (m, 2H); MS (ES ^<+> ) 508 (M + 1).

The representative compounds of the present invention listed in Table 8 below along with the corresponding measured MS (ES ⁺ ) (M + 1) molecular ion mass numbers are replaced with reagents that can be appropriately replaced according to the procedure described in Example 7 above. It was prepared similarly by selecting and using.

(Example 8)
(S) -2- (3- (2-Amino-N-methyl-3- (thiophen-2-yl) propanamido) propyl) -N- (3,4-dimethoxyphenyl) -1H-indole-5 Carboxamide (Compound # 106)

Step A: Pent-4-ynyl-carbamic acid tert-butyl ester A 1 L round bottom flask was charged with pent-4-yn-1-amine (10.0 g, 0.120 mol), dichloromethane (600 mL), and triethylamine (33 .6 mL, 0.241 mol) and the resulting mixture was cooled in an ice / water bath. Di-tert-butyl dicarbonate (38.4 g, 0.176 mol) was added in three portions and the resulting mixture was stirred at room temperature for 72 hours. The resulting mixture was then concentrated under reduced pressure and the residue was purified by flash silica gel chromatography (Analogix IF-280, SF 65-400 g column, gradient 90: 10-80: 20 heptane: EtOAc) and pent- 4-Inyl-carbamic acid tert-butyl ester was obtained. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.20 to 3.26 (m, 2H), 2.21 to 2.27 (m, 2H), 1.97 (s, 1H), 1.67 to 1 .82 (m, 2H) and 1.44 (s, 9H).

Step B: Methyl-pent-4-ynyl-carbamic acid tert-butyl ester In a 500 mL round bottom flask, pent-4-ynyl-carbamic acid tert-butyl ester (5.0 g, 27.3 mmol) and tetrahydrofuran (138 mL). And the resulting mixture was cooled in an ice / water bath. Sodium hydride (830 mg, 32.9 mmol) was added in three portions and the resulting mixture was stirred at room temperature for 20 minutes. Methyl iodide (8.6 mL, 138.1 mmol) was added slowly and the resulting mixture was stirred for 72 hours. The resulting mixture was diluted with dichlormethane (350 mL) and washed with 1N HCl (100 mL), 1N NaOH (100 mL), and then water (100 mL). The organic layer was washed with MgSO ₄ , filtered, and then concentrated under reduced pressure to give methyl-pent-4-ynyl-carbamic acid tert-butyl ester. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.31 (t, J = 7.0 Hz, 2H), 2.86 (s, 3H), 2.17 to 2.24 (m, 2H), 1.96 (S, 1H), 1.72-1.79 (m, 2H), and 1.46 (s, 9H).

Step C: {5- [2-Amino-5- (3,4-dimethoxy-phenylcarbamoyl) -phenyl] -pent-4-ynyl} -methyl-carbamic acid tert-butyl ester Into a 500 mL round bottom flask was added methyl. -Pent-4-ynyl-carbamic acid tert-butyl ester (1.70 g, 8.62 mmol), 4-amino-N- (3,4-dimethoxyphenyl) -3-iodobenzamide (3.0 g, 7.53 mmol) ), Copper iodide (0.225 g, 1.18 mmol), palladium tetrakistriphenylphosphine (0.93 g, 0.805 mmol), and diethylamine (258 mL), and the resulting mixture was stirred at room temperature for 24 hours. The resulting mixture was then concentrated under reduced pressure and the residue was purified by flash silica gel chromatography (Analogix IF-280, SF 40-400 g column, gradient 90: 10-10: 90 heptane: EtOAc), {5 -[2-Amino-5- (3,4-dimethoxy-phenylcarbamoyl) -phenyl] -pent-4-ynyl} -methyl-carbamic acid tert-butyl ester was obtained. MS (ES ^<+> ) 468 (M + 1).

Step D: tert-Butyl 3- (5- (3,4-dimethoxyphenylcarbamoyl) -1H-indol-2-yl) propyl (methyl) carbamate In a 500 mL round bottom flask, add {5- [2-amino-5 -(3,4-Dimethoxy-phenylcarbamoyl) -phenyl] -pent-4-ynyl} -methyl-carbamic acid tert-butyl ester (3.4 g, 7.27 mmol), dichlorobis (benzonitrile) palladium (II) ( 0.558 g, 1.45 mmol), and dimethylformamide (80 mL) were added and the resulting mixture was heated to 80 ° C. for 24 hours. The resulting mixture was then concentrated under reduced pressure and the residue was purified by flash silica gel chromatography (Analogix IF-280, SF25-40 g column, gradient 90: 10-10: 90 heptane: EtOAc) and tert- Butyl 3- (5- (3,4-dimethoxyphenylcarbamoyl) -1H-indol-2-yl) propyl (methyl) carbamate was obtained. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.84 (s, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.57 (s, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 8.6 Hz, 1H), 6.85 (d, J = 8.6 Hz, 1H), 6.32 (s, 1H), 3.93. (S, 3H), 3.89 (s, 3H), 3.31-3.41 (m, 2H), 2.89 (s, 3H), 2.66-2.77 (m, 2H), 1.83 to 1.94 (m, 2H) and 1.53 (s, 9H). MS (ES ^<+> ) 468 (M + 1).

Step E: 2- (3-M ethylamino-propyl) -1H-indole-5-carboxylic acid (3,4-dimethoxy-phenyl) -amide A 250 mL round bottom flask was charged with tert-butyl 3- (5- ( 3,4-Dimethoxyphenylcarbamoyl) -1H-indol-2-yl) propyl (methyl) carbamate (2.75 g, 5.88 mmol), dichloromethane (32 mL), and 1M hydrochloric acid in diethyl ether (32 mL) were added, The resulting mixture was stirred for 2.5 hours. The resulting mixture was then concentrated under reduced pressure and the residue was triturated with diethyl ether and placed under high vacuum to give 2- (3-methylamino-propyl) -1H-indole-5-carboxylic acid ( 3,4-Dimethoxy-phenyl) -amide was obtained. MS (ES ⁺ ) 368 (M + 1); HPLC: Kromasil C18 column (50 × 2 mm; 3.5 μ), (MeCN + 0.16% TFA) gradient 10-90 in (water + 0.2% TFA) over 4 minutes. %, T _R = 2.72 min.

Step F: [1-({3- [5- (3,4-Dimethoxy-phenylcarbamoyl) -1H-indol-2-yl] -propyl} -methyl-carbamoyl) -2-thiophen-2-yl-ethyl ]-(S) -carbamic acid tert-butyl ester In a 250 mL round bottom flask, add 2- (3-methylamino-propyl) -1H-indole-5-carboxylic acid (3,4-dimethoxy-phenyl) -amide. (2.30 g, 5.70 mmol), 1-hydroxybenzotriazole hydrate (780 mg, 0.553 mmol), N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride (1.65 g, 8. 61 mmol), and dichlormethane (30 mL). Triethylamine (2.6 mL, 18.7 mmol) was added and the resulting mixture was stirred at room temperature for 20 minutes. (S) -2- (tert-Butoxycarbonylamino) -3- (thiophen-2-yl) propanoic acid (1.6 g, 5.90 mmol) was added and the resulting mixture was stirred at room temperature for 24 hours. The resulting mixture was then concentrated under reduced pressure and the residue was purified by flash silica gel chromatography (Analogix IF-280, SF25-40 g column, heptane: EtOAc gradient 90: 10-5: 95) [1 -({3- [5- (3,4-Dimethoxy-phenylcarbamoyl) -1H-indol-2-yl] -propyl} -methyl-carbamoyl) -2-thiophen-2-yl-ethyl]-(S) -Carbamic acid tert-butyl ester was obtained. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.85 (s, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.58 (s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 8.6 Hz, 1H), 6.90 (d, J = 8.6 Hz, 1H), 6.73 to 6.87 (m, 3H) 6.30 (s, 1H), 3.94 (s, 3H), 3.89 (s, 3H), 3.78 to 3.87 (m, 1H), 3.30 to 3.43 (m) , 2H), 2.93 (s, 3H), 2.61 to 2.76 (m, 2H), 1.81 to 1.93 (m, 2H), and 1.43 (s, 9H). MS (ES ^<+> ) 621 (M + 1).

Step G: (S) -2- (3- (2-Amino-N-methyl-3- (thiophen-2-yl) propanamido) propyl) -N- (3,4-dimethoxyphenyl) -1H-indole -5-carboxamide In a 50 mL round bottom flask was added [1-({3- [5- (3,4-dimethoxy-phenylcarbamoyl) -1H-indol-2-yl] -propyl} -methyl-carbamoyl) -2. -Thiophen-2-yl-ethyl]-(S) -carbamic acid tert-butyl ester (3.26 g, 2.52 mmol) and dichloromethane (36 mL) were added. 1M hydrochloric acid in diethyl ether (26 mL) was added and the resulting mixture was stirred at room temperature for 2.5 hours. The resulting mixture was then concentrated under reduced pressure to give (S) -2- (3- (2-amino-N-methyl-3- (thiophen-2-yl) propanamido) propyl) -N- (3 4-Dimethoxyphenyl) -1H-indole-5-carboxamide was obtained. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.66-7.80 (m, 1H), 7.54 (s, 1H), 7.35-7.46 (m, 3H), 6.84 To 7.21 (m, 4H), 6.31 (s, 1H), 3.86 to 3.97 (m, 1H), 3.76 (s, 3H), 3.74 (s, 3H), 3.22-3.52 (m, 4H), 2.82 (s, 3H), 2.58-2.70 (m, 2H), and 1.79-1.89 (m, 2H); MS (ES ⁺ ) 521 (M + 1); C ₂₈ H ₃₂ N ₄ O ₄ S · 1.25 HCl · 0.9 H ₂ O calculated: C, 57.74; H, 6.17; N, 9 .35; Cl, 7.56; H ₂ O, 2.72. Found: C, 57.65; H, 6.07 ; N, 9.62; Cl, 7.61; H 2 O, 2.78.

The representative compounds of the present invention listed in Table 9 below along with the corresponding measured MS (ES ⁺ ) (M + 1) molecular ion mass numbers are replaced with reagents that can be appropriately replaced according to the procedure described in Example 8 above. It was prepared similarly by selecting and using.

Example 9
(S) -N- (2- (1H-benzo [d] imidazol-2-yl) ethyl) -2-amino-3- (thiophen-2-yl) propanamide (Compound # 37)

Step A: {1- [2- (1H-Benzimidazol-2-yl) -ethylcarbamoyl] -2-thiophen-2-yl-ethyl}-(S) -carbamic acid tert-butyl ester 50 mL round bottom flask (S) -2- (tert-butoxycarbonylamino) -3- (thiophen-2-yl) propanoic acid (300 mg, 1.10 mmol), 1-hydroxybenzotriazole hydrate (75 mg, 0.55 mmol) , O-benzotriazole e-N, N, N ′, N′-tetramethyl-uronium-hexafluorophosphate (500 mg, 1.33 mmol), and dimethylformamide (5.0 mL). Triethylamine (0.77 mL, 0.55 mmol) and 2- (1H-benzo [d] imidazol-2-yl) ethanamine (388.2 mg, 1.66 mmol) were added and the resulting mixture was stirred at room temperature for 22 hours. did. The resulting mixture was then concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (ISCO, SF 25-40 g column, gradient 90: 10-75: 25 heptane: EtOAc), {1- [2 -(1H-Benzimidazol-2-yl) -ethylcarbamoyl] -2-thiophen-2-yl-ethyl}-(S) -carbamic acid tert-butyl ester was obtained. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.73-7.69 (m, 2H), 7.29-7.37 (m, 2H), 7.54-7.33 (m, 4H), 7 .11 (d, J = 8.2 Hz, 1H), 6.82 to 6.88 (m, 2H), 5.32 (t, J = 3.71 Hz, 1H), 4.33 (m, 1H) 3.78-3.97 (s, 2H), 3.45-3.35 (m, 2H), 3.15-2.91 (m, 4H), and 1.41-1.21 (m , 9H); MS (ES ⁺ ) 415 (M + 1).

Step B: (S) -N- (2- (1H-benzo [d] imidazol-2-yl) ethyl) -2-amino-3- (thiophen-2-yl) propanamide In a 50 mL round bottom flask, {1- [2- (1H-Benzimidazol-2-yl) -ethylcarbamoyl] -2-thiophen-2-yl-ethyl}-(S) -carbamic acid tert-butyl ester (100.0 mg, 0.24 mmol ), And dichloromethane (4 mL). 1M trifluoroacetitic acid (1 mL) was added and the resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was then concentrated under reduced pressure and the residue (oil) was Gilson HPLC (10u, 100Å C18, column length 250 x 50 mm, gradient 0-60 MeCN: H ₂ O) equipped with a reverse phase Kromasil column. Purified above. The resulting solid was taken up in dichloromethane and treated with 1M hydrochloric acid in diethyl ether. The resulting mixture was concentrated under reduced pressure and this procedure was repeated twice more to (S) -N- (2- (1H-benzo [d] imidazol-2-yl) ethyl) -2-amino-3- (Thiophen-2-yl) propanamide was obtained. ¹ H NMR (300 MHz, MeOH-d4) δ 7.89-7.75 (m, 2H), 7.69-7.58 (d, 2H), 7.32-7.21 (d, J = 8 .2 Hz, 1H), 6.99-6.91 (m, 2H), 4.03 (t, J = 3.71 Hz, 1H), 3.75-3.89 (m, 2H), 3.59 -3.3.31 (m, 4H), 3.04 (s, 1H), 2.64-2.79 (m, 2H), 2.80 (s, 1H); MS (ES ⁺ ) 315 ( M + 1).

Representative compounds of the present invention listed in Table 10 below along with corresponding measured MS (ES ⁺ ) (M + 1) molecular ion mass numbers are substituted with reagents that are appropriately replaced according to the procedure described in Example 9 above. It was prepared similarly by selecting and using.

(Example 10)
(S) -2-Amino-1- (4- (5- (3,4-dimethoxyphenyl) -1H-benzo [d] imidazol-2-yl) piperidin-1-yl) -3- (thiophene-2 -Yl) propan-1-one (compound # 18)

Step A: (S) -tert-butyl 1- (4- (5-bromo-1H-benzo [d] imidazol-2-yl) piperidin-1-yl) -1-oxo-3- (thiophen-2- Yl) propan-2-ylcarbamate In a 250 mL round bottom flask was added (S) -2- (tert-butoxycarbonylamino) -3- (thiophen-2-yl) propanoic acid (569.0 mg, 0.2.10 mmol). ), 1-hydroxybenzotriazole hydrate (142.0 mg, 1.05 mmol), O-benzotriazol-1-yl-N, N, N′N′-tetramethyluronium hexafluorophosphate (1025.0 mg, 2.73 mmol) and dimethylformamide (7.0 mL) were added. Triethylamine (1.17 mL, 8.39 mmol) and 5-bromo-2-piperidin-4-yl-1H-benzimidazole hydrochloride (730.0 mg, 2.306 mmol) were added and the resulting mixture was stirred at room temperature for 22 hours. Stir for hours. The resulting mixture was then concentrated under reduced pressure and the residue was purified by reverse phase HPLC (“RPHPLC”) (gradient 20-90, MeCN to water) to give (S) -tert-butyl 1- ( 4- (5-Bromo-1H-benzo [d] imidazol-2-yl) piperidin-1-yl) -1-oxo-3- (thiophen-2-yl) propan-2-ylcarbamate and its corresponding Obtained as the trifluoroacetate salt. 1H NMR (300 MHz, DMSO-D6) δ 7.92 (s, 1H), 7.65 (m, 1H), 7.54 (m, 1H), 7.32-7.25 (m, 2H), 6.96-6.91 (m, 2H), 4.65 (m, 1H), 4.42-4.15 (m, 2H), 3.31-3.11 (m, 4H), 2. 99 (m, 1H), 2.15 to 2.61 (m, 2H), and 1.73 (m, 2H), 1.43 (s, 9H); MS (ES +) 648 (M + 1).

Step B: (2- {4- [5- (3,4-Dimethoxy-phenyl) -1H-benzimidazol-2-yl] -piperidin-1-yl} -2-oxo-1-thiophen-2-ylmethyl -Ethyl)-(S) -carbamic acid tert-butyl ester In a 10 mL sealed tube, (S) -tert-butyl 1- (4- (5-bromo-1H-benzo [d] imidazol-2-yl) piperidine -1-yl) -1-oxo-3- (thiophen-2-yl) propan-2-ylcarbamate (200 mg, 0.31 mmol), 3,4-dimethoxyphenylboronic acid (67.5 mg, 0.37 mmol) 1,1′-bis (di-t-butylphophino) ferrocene palladium dichloride (10.07 mg, 0.015 mmol), 10% carbonic acid Thorium aqueous (0.82 mL), and was placed in 1,4-dioxane (2 mL). The vessel was then flushed with argon and sealed. The resulting mixture was stirred at 100 ° C. for 24 hours, then diluted with dichloromethane (300 mL) and washed with water (10 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated, the residue was purified by RPHPLC (15-90, gradient, MeCN-water), dried under reduced pressure and (2- {4- [ 5- (3,4-Dimethoxy-phenyl) -1H-benzimidazol-2-yl] -piperidin-1-yl} -2-oxo-1-thiophen-2-ylmethyl-ethyl)-(S) -carbamic acid The tert-butyl ester was obtained as its corresponding trifluoroacetate salt. MS (ES ^<+> ) 591 (M + 1).

Step C: (S) -2-Amino-1- (4- (5- (3,4-dimethoxyphenyl) -1H-benzo [d] imidazol-2-yl) piperidin-1-yl) -3- ( Thiophen-2-yl) propan-1-one In a 25 mL round bottom flask was added (2- {4- [5- (3,4-dimethoxy-phenyl) -1H-benzimidazole-2-] as the trifluoroacetate salt. Yl] -piperidin-1-yl} -2-oxo-1-thiophen-2-ylmethyl-ethyl)-(S) -carbamic acid tert-butyl ester (230 mg, 0.326 mmol) and 1,4-dioxane (1 5 mL). 4M Hydrochloric acid in 1,4-dioxane (1.63 mL) was added and the resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was then concentrated under reduced pressure to give (S) -2-amino-1- (4- (5- (3,4-dimethoxyphenyl) -1H-benzo [d] imidazol-2-yl) piperidine. -1-yl) -3- (thiophen-2-yl) propan-1-one was obtained. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.45 (m, 2H), 7.91-7.85 (m, 2H), 7.61-7.58 (d, J = 8.4 Hz, 1H), 7.3-7.2 (m, 2H), 6.85-7.0 (m, 3H), 4.75 (m, 1H), 4.52-4.13 (m, 2H) 3.96-3.84 (s, 6H), 3.43-3.33 (m, 4H), 2.96 (m, 1H), 2.24-1.86 (m, 4H); MS (ES ⁺ ) 491 (M + 1). g

Representative compounds of the present invention listed in Table 11 below along with the corresponding measured MS (ES ⁺ ) (M + 1) molecular ion mass numbers are replaced with reagents that can be appropriately replaced according to the procedure described in Example 9 above. It was prepared similarly by selecting and using.

(Example 11)
(S) -2-Amino-N- (3- (5- (3,4-dimethoxyphenoxy) -1H-indol-2-yl) propyl) butanamide (Compound # 99)

Step A: (1-Pent-4-ynylcarbamoyl-propyl)-(S) -carbamic acid tert-butyl ester Into a 500 mL round bottom flask was added (S) -2- (tert-butoxycarbonylamino) butanoic acid (5 0.0 g, 0.025 mol), 1-hydroxybenzotriazole hydrate (4.5 g, 0.033 mol), N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride (6.4 g, 0.03 mol). 033 mol), 4- (dimethylamino) pyridine (0.02 g, 0.163 mmol), and dimethylformamide (95 mL) were added. Triethylamine (10.6 mL, 0.076 mol) and pent-4-yne-1-amine (2.7 g, 0.033 mol) were added and the resulting mixture was stirred at room temperature for 22 hours. The resulting mixture was then concentrated under reduced pressure and the residue was purified by flash silica gel chromatography (Analogix IF-280, SF 65-400 g column, gradient 90: 10-40: 60 heptane: EtOAc) (1 -Pent-4-ynylcarbamoyl-propyl)-(S) -carbamic acid tert-butyl ester was obtained. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.93-4.00 (m, 1H), 3.36 to 3.42 (m, 2H), 2.22 to 2.28 (m, 2H), 2 0.00 (s, 1H), 1.83 to 1.92 (m, 1H), 1.70 to 1.80 (m, 2H), 1.57 to 1.67 (m, 1H), 1.45 (S, 9H), and 0.94 (t, J = 7.4 Hz, 3H).

Step B: {1- [5- (2-Amino-5-bromo-phenyl) -pent-4-ynylcarbamoyl] -propyl}-(S) -carbamic acid tert-butyl ester In a 50 mL round bottom flask, 1-pent-4-ynylcarbamoyl-propyl)-(S) -carbamic acid tert-butyl ester (2.24 g, 8.36 mmol), 4-bromo-2-iodoaniline (2.38 g, 8.59 mmol), Copper iodide (0.21 g, 1.10 mmol), palladium tetrakistriphenylphosphine (1.12 g, 0.97 mmol), and diethylamine (300 mL) were added, and the resulting mixture was stirred at room temperature for 4 hours. The resulting mixture was then concentrated under reduced pressure and the residue was purified by flash silica gel chromatography (Analogix IF-280, SF 40-400 g column, heptane: EtOAc gradient 90:10 to 10:90), {1 -[5- (2- {1- [5- (2-amino-5-bromo-phenyl) -pent-4-ynylcarbamoyl] -propyl}-(S) -carbamic acid tert-butyl ester amino (tert- butyl ester mino) -5-bromo-phenyl) -pent-4-ynylcarbamoyl] -propyl}-(S) -carbamic acid tert-butyl ester was obtained. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.94 (s, 1H), 7.76 (d, J = 6.5 Hz, 1H), 6.64 (d, J = 8.5 Hz, 1H), 3 .91 to 4.09 (m, 1H), 3.85 (s, 3H), 3.47 to 3.52 (m, 2H), 2.52 (t, J = 6.8 Hz, 2H), 1 .75 to 1.92 (m, 3H), 1.60 to 1.69 (m, 1H), 1.44 (s, 9H), and 0.94 (t, J = 7.4 Hz, 3H); MS (ES ^<+> ) 439 (M + 1).

Step C: (1- {3- [5- (3,4-Dimethoxy-phenoxy) -1H-indol-2-yl] -propylcarbamoyl} -propyl)-(S) -carbamic acid tert-butyl ester In a sealed tube, {1- [5- (2-amino-5-bromo-phenyl) -pent-4-ynylcarbamoyl] -propyl}-(S) -carbamic acid tert-butyl ester (0.5 g, 1. 22 mmol), 3,4-dimethoxyphenylboronic acid (0.28 g, 1.83 mmol), cesium carbonate (0.8 g, 2.44 mmol), N, N-dimethylglycene hydrochloride hydrochloride ( 0.15 g, 1.1 mmol), copper iodide (0.07 g, 0.36 mmol), and 1,4-dioxane (2.5 mL) were added. The vessel was then flushed with argon and sealed, and the resulting mixture was stirred at 120 ° C. for 24 hours. The resulting mixture was then washed with water (25 mL) and extracted with ethyl acetate. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting residue was purified by RPHPLC (gradient 35-90, acetonitrile-water) to give (1- {3- [5- (3,4-dimethoxy-phenoxy) -1H-indol-2-yl]- Propylcarbamoyl} -propyl)-(S) -carbamic acid tert-butyl ester was obtained. ¹ H NMR (300 MHz, CDCl 3) δ 9.51 (s, 1H), 7.12 (s, 1H), 6.94-6.82 (m, 2H), 6.75-6.79 (m, 1H), 6.67-6.63 (d, J = 3.0 Hz, 1H), 6.15 (t, J = 6.0 Hz, 1H), 6.05 (s, 1H), 4.06 ( m, 1H), 3.93 (s, 6H), 3.63-3.31 (m, 2H), 2.74 (m, 2H), 1.81-1.67 (m, 4H), and 1.49 (s, 9H), 0.96 (t, J = 7.0 Hz, 3H); MS (ES ⁺ ) 512 (M + 1).

Process D:
To a 50 mL round bottom flask was added (1- {3- [5- (3,4-dimethoxy-phenoxy) -1H-indol-2-yl] -propylcarbamoyl} -propyl)-(S) -carbamic acid tert- Butyl ester (110 mg, 0.21 mmol) and dichloromethane (3 mL) were added. 1M hydrochloric acid in diethyl ether (3 mL) was added and the resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was then concentrated under reduced pressure to give (S) -2-amino-N- (3- (5- (3,4-dimethoxyphenoxy) -1H-indol-2-yl) propyl) butanamide. It was. ¹ HNMR (300 MHz, DMSO-d ₆ ) δ11 (s, 1H), 8.15 (brs, 1H), 7.29-7.25 (d, J = 9 Hz, 1H), 6.92 (m, 1H) ), 6.81 (d, J = 8 Hz, 1H), 6.72 (m, 2H), 6.85 (m, 1H), 6.15 (s, 1H), 3.73 (s, 6H) 3.65 (m, 1H), 3.37-3.15 (m, 2H), 2.75 (t, J = 7 Hz, 2H), 1.91-1.62 (m, 4H), and 0.97 (t, J = 7.2 Hz, 3H); MS (ES ⁺ ) 412 (M + 1).

Compound # 98 was similarly prepared according to the procedure described in Example 11 above, and the MS (ES ⁺ ) measured was 352 (M + 1).

Biological Example 1: DPP-1 inhibition assay (in vitro)
Test compounds were evaluated for DPP-1 (cathepsin C) inhibitory activity using a fluorogenic substrate, GR-AMC (Glycine-arginine-amino-4-methylcoumarin, Bachem, I-1215). The amount of amino-methylcoumarin released is proportional to DPP-1 activity, and the reaction is monitored kinetically using a Molecular Devices plate reader using black 96 well plates.

  All compounds were tested under room temperature conditions. The assay buffer consists of 50 mM HEPES, pH 7.0, 100 mM NaCl, 2 mM glutathione (GSH), and 0.002% TWEEN 20. GSH and TWEEN 20 were freshly added to the buffer every day. Immediately prior to use, the autogenous preparation of recombinant human DPP-1 (240 μM stock solution, molecular weight 49.6 kD) was diluted 600-fold in assay buffer containing fresh 2 mM dithiothreitol (DTT) to activate the enzyme And then diluted in assay buffer (no DTT) by a factor of 133 to 3 nM DPP-1 working solution. Test compounds were diluted in DMSO to 20 times their final assay concentration.

The additions to the 96 well black Costar 3915 plate are as follows: 90 μL of 11 μM GR-AMC, 5 μL of test compound (following mixing), and 5 μL of 3 nMDPP1 to initiate the reaction. The fluorescence reaction was kinetically monitored on a Molecular Devices Spectramax XPS reader with excitation 360 nm and emission 440 nm. With this reader's software Softmax Pro, the initial rate of the selected data (first 3-5 minutes of the reaction) and the best linear regression fit of the initial dynamic data were determined. Final assay conditions were 0.15 nM DPP-1, 10 uM GR-AMC, 50 mM HEPES, pH 7.0, 100 mM NaCl, 2 mM GSH, 0.002% TWEEN 20, 1 uM DTT, 5 0.0% DMSO. The initial rate ratio was determined using the GraphPad Prism® software with a fixed Hill (1.0) using a four parameter logistic equation (nonlinear regression, sigmoidal dose response (variable slope)). And plotted against test compound concentration for determination of IC ₅₀ of DPP-1. The coefficient of variation (CV) within the assay run was generally <10% and the CV between assay runs was <20%.

  Following the procedures described above, representative compounds of the present invention were tested and the results are listed in Table 12 below. When compounds are tested multiple times according to the procedure described above, the average values are shown in the table below.

^For these compounds, the number of different concentrations tested is not sufficient to calculate IC ₅₀ values other than the determination that it was greater than about 10 μM or greater than 20 μM, as described above. There wasn't.

Solid Oral Formulation-Virtual Example As a specific embodiment of the oral composition, 100 mg of compound # 2 prepared as in Example 6 was formulated with sufficient fine powdered lactose to obtain a total amount of 580-590 mg, Filled into size O hard gel capsules.

  Although the foregoing specification teaches the principles of the invention, along with examples provided for purposes of illustration, the practice of the invention is included within the scope of the following claims and their equivalents. It will be understood to include all the usual variations, adaptations and / or modifications that may be made.

Claims (24)

Formula (I):
[Where,
R ¹ is, C _{1 to 4} alkyl is selected from _{-C (O) -NH 2, C} 3~6 cycloalkyl, the group consisting 及 beauty 5-6 membered heteroaryl, wherein heteroaryl is halogen and C ₁ optionally substituted with one or more substituents independently selected from _{~ 4} alkyl,
n is an integer of 0 to 1,
L is
Selected from the group consisting of —CH ₂ CH ₂ —N (CH ₃ ) —, —CH ₂ CH ₂ —N (CH ₂ CH ₃ ) —, and —CH ₂ CH ₂ CH ₂ —NR ^A —, R ^A is selected from the group consisting of hydrogen, methyl, and ethyl;
Y is selected from the group consisting of N and CH;
X is selected from the group consisting of N (R ^B ), O, and S, wherein R ^B is selected from the group consisting of hydrogen and C _1-4 alkyl;
R ² is selected from the group consisting of hydrogen, halogen, nitro, —CO ₂ H, —C (O) —NR ^C R ^D , —Q, —O—Q, and —C (O) —NH—Q. ,
Where R ^C and R ^D are each independently selected from the group consisting of hydrogen and C _1-4 alkyl, or R ^C and R ^D together with the nitrogen atom to which they are attached. Piperidin-1-ylpiperazin-1-yl, pyrrolidin-1-yl, morpholin-4-yl, 1,2,3,4-tetrahydronolin-1-yl, and 1,2,3,4-tetrahydro- Forming a cyclic structure selected from the group consisting of isoquinolin-2-yl,
Q is selected from the group consisting of aryl, aralkyl, heterocyclyl, benzo [d] [1,3] dioxolyl, and 2,3-hydro-benzo [b] [1,4] dioxinyl;
The aryl or heterocyclyl, whether alone or as part of a substituent, is halogen, cyano, C _1-4 alkyl, halogenated C _1-4 alkyl, C _1-4 alkoxy, halogenated C One or more substituents independently selected from the group consisting of _1-4 alkoxy, —CO ₂ H, —C (O) —NR ^E R ^F , —SO ₂ —NR ^E R ^F , and phenyl; Optionally substituted, wherein R ^E and R ^F are each independently selected from the group consisting of hydrogen and C _1-4 alkyl;
The heterocyclyl may contain one or more S heteroatoms, and the heterocyclyl may be further optionally substituted with 1-2 oxo groups on the one or more S heteroatoms. ]
Or a pharmaceutically acceptable salt thereof. A compound according to claim 1, comprising:
R ¹ is selected from the group consisting of C _1-4 alkyl, —C (O) —NH ₂ , C _3-6 cycloalkyl, and 5-6 membered heteroaryl, wherein said 5-6 membered heteroaryl Is optionally substituted with 1 to 2 substituents selected from the group consisting of halogen and C _1-4 alkyl,
n is an integer of 0 to 1,
L is
Selected from the group consisting of —CH ₂ CH ₂ —N (CH ₃ ) —, —CH ₂ CH ₂ —N (CH ₂ CH ₃ ) —, and —CH ₂ CH ₂ CH ₂ —N (R ^A ) — Where R ^A is selected from the group consisting of hydrogen, methyl, and ethyl;
Y is selected from the group consisting of N and CH;
X is selected from the group consisting of N (R ^B ), O and S, wherein R ^B is selected from the group consisting of hydrogen and C _1-2 alkyl;
R ² is selected from the group consisting of hydrogen, halogen, nitro, —CO ₂ H, —C (O) —NR ^C R ^D , phenyl, —O-phenyl, heterocyclyl, and —C (O) —NH—Q. And
Where R ^C and R ^D are each independently selected from the group consisting of hydrogen and C _1-4 alkyl, or R ^C and R ^D together with the nitrogen atom to which they are attached. , Piperidin-1-yl, pyrrolidin-1-yl, 1,2,3,4-tetrahydroquinolin-1-yl, and 1,2,3,4-tetrahydro-isoquinolin-2-yl Forming a ring structure,
Q is selected from the group consisting of aryl, aralkyl, heterocyclyl, benzo [d] [1,3] dioxolyl, and 2,3-dihydro-benzo [b] [1,4] dioxinyl;
The aryl or heterocyclyl, whether alone or as part of a substituent, is halogen, cyano, C _1-4 alkyl, fluorinated C _1-4 alkyl, C _1-4 alkoxy, fluorinated C _{1-4 alkoxy, -CO 2 H, -C (O} ) NR E R F, are independently selected from -SO ₂ -NR ^E R ^F, and the group consisting of phenyl, with one to two substituents Optionally substituted, wherein R ^E and R ^F are each independently selected from the group consisting of hydrogen and C _1-2 alkyl;
The heterocyclyl contains one or more S heteroatoms, and the heterocyclyl may be further optionally substituted with 1-2 oxo groups on the one or more S heteroatoms,
Said compound, or a pharmaceutically acceptable salt thereof. A compound according to claim 2, comprising
R ¹ is selected from the group consisting of C _1-4 alkyl, —C (O) —NH ₂ , C _4-6 cycloalkyl, and 5-6 membered heteroaryl, wherein said 5-6 membered heteroaryl Is optionally substituted with a substituent selected from the group consisting of halogen and C _1-4 alkyl,
n is an integer of 0 to 1,
L is
Selected from the group consisting of —CH ₂ CH ₂ —N (CH ₃ ) —, —CH ₂ CH ₂ —N (CH ₂ CH ₃ ) —, and —CH ₂ CH ₂ CH ₂ —N (R ^A ) — Where R ^A is selected from the group consisting of hydrogen, methyl and ethyl;
Y is selected from the group consisting of N and CH;
X is selected from the group consisting of N (R ^B ) and O, wherein R ^B is selected from the group consisting of hydrogen and C _1-2 alkyl;
R ² is selected from the group consisting of hydrogen, halogen, nitro, carboxy, phenyl, —O-phenyl, —C (O) —NR ^C R ^D , and —C (O) —NH—Q;
Where R ^C and R ^D are each independently selected from the group consisting of hydrogen and C _1-2 alkyl, or R ^C and R ^D together with the nitrogen atom to which they are attached. Forming a cyclic structure selected from the group consisting of 1,2,3,4-tetrahydro-quinolin-1-yl and 1,2,3,4-tetrahydroisoquinolin-2-yl,
Q is from the group consisting of phenyl, naphthyl, —C _1-2 alkyl-phenyl, heterocyclyl, benzo [d] [1,3] dioxolyl, and 2,3-dihydro-benzo [b] [1,4] dioxinyl. Selected
The phenyl or heterocyclyl, whether alone or as part of a substituent, is halogen, cyano, C _1-4 alkyl, fluorinated C _1-2 alkyl, C _1-4 alkoxy, fluorinated C _{1-2 alkoxy, -CO 2 H, -C (O} ) NH 2, are independently selected from -SO ₂ -NH _2, and the group consisting of phenyl, being optionally substituted with one to two substituents ,
The heterocyclyl contains one or more S heteroatoms, and the heterocyclyl may be further optionally substituted with 1-2 oxo groups on the one or more S heteroatoms,
Said compound, or a pharmaceutically acceptable salt thereof. A compound according to claim 3, wherein
R ¹ is ethyl, cyclobutyl, thien-2-yl, thien-3-yl, 2-bromo-thien-2-yl, 5-chloro-thien-2-yl, thiazol-2-yl, 4-methyl- Selected from the group consisting of thiazol-2-yl, pyrazol-1-yl, fur-2-yl, 1-methyl-imidazol-4-yl, and amino-carbonyl;
n is an integer of 0 to 1,
L is
Selected from the group consisting of —CH ₂ CH ₂ CH ₂ —NH—, —CH ₂ CH ₂ CH ₂ —N (CH ₃ ) — and —CH ₂ CH ₂ CH ₂ —N (CH ₂ CH ₃ ) —
Y is selected from the group consisting of CH and N;
X is selected from the group consisting of NH, N (CH ₃ ), and O;
However, when X is O, Y is CH,
R ² is hydrogen, 5-bromo, 5- (carboxy), 5- (nitro), 5- (phenyl), 5- (4-fluorophenyl), 5- (4-methoxy-phenyl), 5- ( 3,4-dimethoxy-phenyl), 5- (3,5-dimethoxy-phenyl), 5- (3-cyano-phenyl), 5- (3-carboxy-phenyl), 5- (4-carboxy-phenyl) 5- (4-trifluoromethyl-phenyl), 5- (4-trifluoromethoxy-phenyl), 5- (3,5-di (trifluoromethyl) -phenyl), 5- (2- (aminocarbonyl) ) -Phenyl), 5- (3- (aminocarbonyl) -phenyl), 5- (4- (aminocarbonyl) -phenyl), 5- (3- (aminosulfonyl) -phenyl), 5- (phenoxy), 5- (3,4-di Toxi-phenoxy), 6- (diethylamino-carbonyl), 5- (phenyl-amino-carbonyl), 5- (3-chlorophenyl-amino-carbonyl), 5- (4-chlorophenyl-amino-carbonyl), 5- ( 2-fluorophenyl-amino-carbonyl), 5- (3-fluorophenyl-amino-carbonyl), 5- (4-fluorophenyl-amino-carbonyl), 5- (3-methylphenyl-amino-carbonyl), 5 -(4-methylphenyl-amino-carbonyl), 5- (2-isopropylphenyl-amino-carbonyl), 5- (4-isopropylphenyl-amino-carbonyl), 5- (4-t-butylphenyl-amino-) Carbonyl), 5- (2-methoxyphenyl-amino-carbonyl), 5- (3-methoxy Phenyl-amino-carbonyl), 5- (4-methoxyphenyl-amino-carbonyl), 5- (3,4-difluorophenyl-amino-carbonyl), 5- (3,4-dichlorophenyl-amino-carbonyl), 5 -(3,4-dimethylphenyl-amino-carbonyl), 5- (2,6-dimethylphenyl-amino-carbonyl), 5- (3,4-dimethoxyphenyl-amino-carbonyl), 5- (3,5 -Dimethoxyphenyl-amino-carbonyl), 5- (naphth-1-yl-amino-carbonyl), 5- (benzyl-amino-carbonyl), 5-([1,2,4] triazol-3-yl-amino -Carbonyl), 5- (pyrid-3-yl-amino-carbonyl), 5- (quinolin-3-yl-amino-carbonyl), 5- (quino) -5-yl-amino-carbonyl), 5-quinolin-6-yl-amino-carbonyl), 5- (quinolin-8-yl-amino-carbonyl), 5- (isoquinolin-5-yl-amino-carbonyl) ), 5- (isoquinolin-8-yl-amino-carbonyl), 5- (benzothiazol-6-yl-amino-carbonyl), 5- (benzimidazol-4-yl-amino-carbonyl), 5- (benz Imidazol-5-yl-amino-carbonyl), 5- (1-methyl-benzimidazol-4-yl-amino-carbonyl), 5- (pyrazol-3-yl-amino-carbonyl), 5- (5-phenyl) -Pyrazol-3-yl-amino-carbonyl), 5- (1H-pyrazolo [3,4-d] pyrimidin-4-yl-amino-carbonyl) , 5- (1,1-dioxo-benzothiophen-6-yl-amino-carbonyl), 5- (1,2,3,4-tetrahydro-quinolin-1-yl-amino-carbonyl), 5- (1 , 2,3,4-tetrahydro-quinolin-1-yl-carbonyl), 5- (1,2,3,4-tetrahydro-isoquinolin-2-yl-carbonyl), 5- (pyrid-3-yl), 5- (pyrid-4-yl), 5- (6-methoxy-pyrid-3-yl), 5- (2,3-dihydro-benzo [b] [1,4] dioxin-6-yl), and Selected from the group consisting of 5- (benzo [d] [1,3] dioxol-5-yl);
Said compound, or a pharmaceutically acceptable salt thereof. A compound according to claim 4, comprising:
R ¹ is selected from the group consisting of ethyl, thien-2-yl, thiazol-2-yl, fur-2-yl, and 1-methyl-imidazol-4-yl;
n is an integer of 0 to 1,
L is
Selected from the group consisting of —CH ₂ CH ₂ CH ₂ —NH—, and —CH ₂ CH ₂ CH ₂ —N (CH ₂ CH ₃ ) —
Y is selected from the group consisting of CH and N;
X is selected from the group consisting of NH and O;
However, when X is O, Y is CH,
R ² is hydrogen, 5-bromo, 5- (phenyl), 5- (4-fluorophenyl), 5- (4-methoxy-phenyl), 5- (3,4-dimethoxy-phenyl), 5- ( 3,5-dimethoxy-phenyl), 5- (3-cyano-phenyl), 5- (3-carboxy-phenyl), 5- (4-carboxy-phenyl), 5- (4-trifluoromethyl-phenyl) , 5- (4-trifluoromethoxy-phenyl), 5- (3,5-di (trifluoromethyl) -phenyl), 5- (2- (aminocarbonyl) -phenyl), 5- (3- (amino Carbonyl) -phenyl), 5- (4- (aminocarbonyl) -phenyl), 5- (3- (aminosulfonyl) -phenyl), 5- (phenoxy), 5- (3,4-dimethoxy-phenoxy), 5- (Feni -Amino-carbonyl), 5- (3-chlorophenyl-amino-carbonyl), 5- (4-chlorophenyl-amino-carbonyl), 5- (2-fluorophenyl-amino-carbonyl), 5- (3-fluorophenyl) -Amino-carbonyl), 5- (4-fluorophenyl-amino-carbonyl), 5- (3-methylphenyl-amino-carbonyl), 5- (4-methylphenyl-amino-carbonyl), 5- (2- Isopropylphenyl-amino-carbonyl), 5- (4-isopropylphenyl-amino-carbonyl), 5- (4-t-butylphenyl-amino-carbonyl), 5- (2-methoxyphenyl-amino-carbonyl), 5 -(3-methoxyphenyl-amino-carbonyl), 5- (4-methoxyphenyl-amino-cal Bonyl), 5- (3,4-difluorophenyl-amino-carbonyl), 5- (3,4-dichlorophenyl-amino-carbonyl), 5- (3,4-dimethylphenyl-amino-carbonyl), 5- ( 2,6-dimethylphenyl-amino-carbonyl), 5- (3,4-dimethoxyphenyl-amino-carbonyl), 5- (3,5-dimethoxyphenyl-amino-carbonyl), 5- (naphth-1-yl) -Amino-carbonyl), 5- (pyrid-3-yl-amino-carbonyl), 5- (quinolin-3-yl-amino-carbonyl), 5- (quinolin-5-yl-amino-carbonyl), 5- (Quinolin-6-yl-amino-carbonyl), 5- (quinolin-8-yl-amino-carbonyl), 5- (isoquinolin-5-yl-amino-cal) Nyl), 5- (isoquinolin-8-yl-amino-carbonyl), 5- (benzothiazol-6-yl-amino-carbonyl), 5- (benzimidazol-4-yl-amino-carbonyl), 5- ( Benzimidazol-5-yl-amino-carbonyl), 5- (1-methyl-benzimidazol-4-yl-amino-carbonyl), 5- (pyrazol-3-yl-amino-carbonyl), 5- (5- Phenyl-pyrazol-3-yl-amino-carbonyl), 5- (1H-pyrazolo [3,4-d] pyrimidin-4-yl-amino-carbonyl), 5- (1,1-dioxo-benzothiophene-6) -Yl-amino-carbonyl), 5- (1,2,3,4-tetrahydro-quinolin-1-yl-amino-carbonyl), 5- (1,2,3, -Tetrahydro-quinolin-1-yl-carbonyl), 5- (1,2,3,4-tetrahydro-isoquinolin-2-yl-carbonyl), 5- (pyrid-3-yl), 5- (pyrid-4) -Yl), 5- (6-methoxy-pyrid-3-yl), 5- (2,3-dihydro-benzo [b] [1,4] dioxin-6-yl), and 5- (benzo [d ] [1,3] dioxol-5-yl)
The stereocenter of the star is present in (S) the enantiomeric excess of the configuration,
Said compound, or a pharmaceutically acceptable salt thereof. A compound according to claim 4, comprising:
R ¹ is selected from the group consisting of ethyl, thien-2-yl, thiazol-2-yl, and fur-2-yl;
n is an integer of 0 to 1,
L is
Selected from the group consisting of —CH ₂ CH ₂ CH ₂ —NH—, and —CH ₂ CH ₂ CH ₂ —N (CH ₂ CH ₃ ) —
Y is selected from the group consisting of CH and N;
X is selected from the group consisting of NH and O;
However, when X is O, Y is CH,
R ² is 5-bromo, 5- (phenyl), 5- (4-fluorophenyl), 5- (4-methoxy-phenyl), 5- (3,4-dimethoxy-phenyl), 5- (3 5-dimethoxy-phenyl), 5- (3-cyano-phenyl), 5- (3-carboxy-phenyl), 5- (4-carboxy-phenyl), 5- (4-trifluoromethyl-phenyl), 5 -(4-trifluoromethoxy-phenyl), 5- (3,5-di (trifluoromethyl) -phenyl), 5- (3- (aminocarbonyl) -phenyl), 5- (4- (aminocarbonyl) -Phenyl), 5- (3- (aminosulfonyl) -phenyl), 5- (phenoxy), 5- (3,4-dimethoxy-phenoxy), 5- (3-chlorophenyl-amino-carbonyl), 5- ( 4-black Phenyl-amino-carbonyl), 5- (3-fluorophenyl-amino-carbonyl), 5- (3-methylphenyl-amino-carbonyl), 5- (4-isopropylphenyl-amino-carbonyl), 5- (4 -T-butylphenyl-amino-carbonyl), 5- (3-methoxyphenyl-amino-carbonyl), 5- (4-methoxyphenyl-amino-carbonyl), 5- (3,4-difluorophenyl-amino-carbonyl) ), 5- (3,4-dichlorophenyl-amino-carbonyl), 5- (3,4-dimethylphenyl-amino-carbonyl), 5- (2,6-dimethylphenyl-amino-carbonyl), 5- (3 , 4-Dimethoxyphenyl-amino-carbonyl), 5- (naphth-1-yl-amino-carbonyl), 5- (quino Phosphorus-3-yl-amino-carbonyl), 5- (quinolin-5-yl-amino-carbonyl), 5- (quinolin-6-yl-amino-carbonyl), 5- (quinolin-8-yl-amino-) Carbonyl), 5- (isoquinolin-5-yl-amino-carbonyl), 5- (isoquinolin-8-yl-amino-carbonyl), 5- (benzothiazol-6-yl-amino-carbonyl), 5- (pyrido -3-yl), 5- (pyrid-4-yl), 5- (6-methoxy-pyrid-3-yl), 5- (2,3-dihydro-benzo [b] [1,4] dioxin- 6-yl), and 5- (benzo [d] [1,3] dioxol-5-yl)
The stereocenter of the star is present in (S) the enantiomeric excess of the configuration,
Said compound, or a pharmaceutically acceptable salt thereof. A compound according to claim 4, comprising:
R ¹ is selected from the group consisting of ethyl, thien-2-yl, and thiazol-2-yl;
n is an integer of 0 to 1,
L is
Selected from the group consisting of —CH ₂ CH ₂ CH ₂ —NH—, and —CH ₂ CH ₂ CH ₂ —N (CH ₂ CH ₃ ) —
Y is selected from the group consisting of CH and N;
X is selected from the group consisting of NH and O;
However, when X is O, Y is CH,
R ² is 5- (4-methoxy-phenyl), 5- (3,4-dimethoxy-phenyl), 5- (3,5-dimethoxy-phenyl), 5- (3-cyano-phenyl), 5- (4-carboxy-phenyl), 5- (3- (aminocarbonyl) -phenyl), 5- (phenoxy), 5- (3,4-dimethoxy-phenoxy), 5- (3-methoxyphenyl-amino-carbonyl ), 5- (4-methoxyphenyl-amino-carbonyl), 5- (2,6-dimethylphenyl-amino-carbonyl), 5- (3,4-dimethoxyphenyl-amino-carbonyl), 5- (quinoline- 3-yl-amino-carbonyl), 5- (quinolin-5-yl-amino-carbonyl), 5- (quinolin-6-yl-amino-carbonyl), 5- (isoquinolin-5-yl) Amino-carbonyl), 5- (isoquinolin-8-yl-amino-carbonyl), 5- (pyrid-3-yl), 5- (pyrid-4-yl), 5- (6-methoxy-pyrido-3- Yl), 5- (2,3-dihydro-benzo [b] [1,4] dioxin-6-yl), and 5- (benzo [d] [1,3] dioxol-5-yl). Selected from
The stereocenter of the star is present in (S) the enantiomeric excess of the configuration,
Said compound, or a pharmaceutically acceptable salt thereof. A compound according to claim 4, comprising:
R ¹ is thien-2-yl, n is 1, and L is
And —CH ₂ CH ₂ CH ₂ —NH—, Y is CH, X is NH, and R ² is 5- (3,4-dimethoxyphenyl) and 5- (3, 4-dimethoxyphenyl-amino-carbonyl), and the asterisk stereocenter is present in enantiomeric excess of (S) configuration,
Said compound, or a pharmaceutically acceptable salt thereof. The compound according to claim 1, wherein the stereocenter of the star is present in an enantiomeric excess of (S) configuration. The compound of formula (I) is
The compound of claim 1, wherein   A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of claim 1.   A pharmaceutical composition produced by mixing the compound according to claim 1 and a pharmaceutically acceptable carrier.   A method for producing a pharmaceutical composition comprising mixing the compound of claim 1 and a pharmaceutically acceptable carrier.   (A) rheumatoid arthritis, (b) asthma, (c) chronic obstructive pulmonary disease, (d) sepsis, (e) irritable bowel disease, (f) cystic fibrosis, or (g) abdominal aortic aneurysm Use of a compound according to claim 1 for the preparation of a medicament for treating them in a patient in need of treatment. Formula (II):
[Where,
R ¹ is C _1-4 alkyl, —C (O) —NH ₂ ,
One or more substitutions selected from the group consisting of C _3-6 cycloalkyl, phenyl, and 5-6 membered heteroaryl, wherein said heteroaryl is independently selected from halogen and C _1-4 alkyl Optionally substituted with a group,
n is an integer of 0 to 1,
L is selected from the group consisting of —CH ₂ CH ₂ —N (CH ₃ ) —, —CH ₂ CH ₂ —N (CH ₂ CH ₃ ) — and —CH ₂ CH ₂ CH ₂ —NR ^A —, R ^A is selected from the group consisting of hydrogen, methyl, and ethyl;
X is selected from the group consisting of N (R ^B ), O, and S, wherein R ^B is selected from the group consisting of hydrogen and C _1-4 alkyl;
R ² is selected from the group consisting of hydrogen, halogen, nitro, —CO ₂ H, —C (O) —NR ^C R ^D , —Q, —O—Q, and —C (O) —NH—Q. ,
Where R ^C and R ^D are each independently selected from the group consisting of hydrogen and C _1-4 alkyl, or R ^C and R ^D together with the nitrogen atom to which they are attached. Piperidin-1-yl, piperazin-1-yl, pyrrolidin-1-yl, morpholin-4-yl, 1,2,3,4-tetrahydroquinolin-1-yl, and 1,2,3,4-tetrahydro -Forming a cyclic structure selected from the group consisting of isoquinolin-2-yl,
Q is selected from the group consisting of aryl, aralkyl, heterocyclyl, benzo [d] [1,3] dioxolyl, and 2,3-dihydro-benzo [b] [1,4] dioxinyl;
The aryl or heterocyclyl, whether alone or as part of a substituent, is halogen, cyano, C _1-4 alkyl, halogenated C _1-4 alkyl, C _1-4 alkoxy, halogenated C One or more substituents independently selected from the group consisting of _1-4 alkoxy, —CO ₂ H, —C (O) —NR ^E R ^F , —SO ₂ —NR ^E R ^F , and phenyl; Optionally substituted, wherein R ^E and R ^F are each independently selected from the group consisting of hydrogen and C _1-4 alkyl;
The heterocyclyl may contain one or more S heteroatoms, and the heterocyclyl may be further optionally substituted with 1-2 oxo groups on the one or more S heteroatoms. ]
Or a pharmaceutically acceptable salt thereof. 16. A compound according to claim 15 , comprising
R ¹ is selected from the group consisting of C _1-4 alkyl, —C (O) —NH ₂ , C _4-6 cycloalkyl, and 5-6 membered heteroaryl, wherein said 5-6 membered heteroaryl Is optionally substituted with one substituent selected from the group consisting of halogen and C _1-4 alkyl,
n is an integer of 0 to 1,
L is selected from the group consisting of —CH ₂ CH ₂ —N (CH ₃ ) —, —CH ₂ CH ₂ —N (CH ₂ CH ₃ ) — and —CH ₂ CH ₂ CH ₂ —NR ^A —, R ^A is selected from the group consisting of hydrogen, methyl, and ethyl;
X is selected from the group consisting of N (R ^B ), O, and S, wherein R ^B is selected from the group consisting of hydrogen and C _1-4 alkyl;
R ² is selected from the group consisting of hydrogen, halogen, nitro, carboxy, phenyl, —O-phenyl, —C (O) —NR ^C R ^D , and —C (O) —NH—Q;
Where R ^C and R ^D are each independently selected from the group consisting of hydrogen and C _1-2 alkyl, or R ^C and R ^D together with the nitrogen atom to which they are attached. , Piperidin-1-yl, pyrrolidin-1-yl, 1,2,3,4-tetrahydroquinolin-1-yl, and 1,2,3,4-tetrahydro-isoquinolin-2-yl Forming a ring structure,
Q is from the group consisting of phenyl, naphthyl, —C _1-2 alkyl-phenyl, heterocyclyl, benzo [d] [1,3] dioxolyl, and 2,3-dihydro-benzo [b] [1,4] dioxinyl. Selected
The phenyl or heterocyclyl, whether alone or as part of a substituent, is halogen, cyano, C _1-4 alkyl, fluorinated C _1-2 alkyl, C _1-4 alkoxy, fluorinated C _{1-2 alkoxy, -CO 2 H, -C (O} ) NH 2, are independently selected from -SO ₂ -NH _2, and the group consisting of phenyl, being optionally substituted with one to two substituents ,
The heterocyclyl contains one or more S heteroatoms, and the heterocyclyl may be further optionally substituted with 1-2 oxo groups on the one or more S heteroatoms,
Said compound, or a pharmaceutically acceptable salt thereof. A compound according to claim 16 , comprising
R ¹ is C _1-4 alkyl, n is 0, X is selected from the group consisting of N (R ^B ) and S, where R ^B consists of hydrogen and C _1-2 alkyl. Selected from the group and R ² is hydrogen;
Said compound, or a pharmaceutically acceptable salt thereof. 18. A compound according to claim 17 , comprising
R ¹ is ethyl, n is 0, X is selected from the group consisting of NH and S, R ² is hydrogen, and the star stereocenter is an enantiomeric excess of (S) configuration Exist in the
Said compound, or a pharmaceutically acceptable salt thereof. The compound of formula (II) is
16. The compound of claim 15, wherein 16. The compound of claim 15 , wherein the star stereocenter is present in an enantiomeric excess of (S) configuration. 16. (a) rheumatoid arthritis, (b) asthma, (c) chronic obstructive pulmonary disease, (d) sepsis, (e) hypersensitivity comprising a pharmaceutically acceptable carrier and the compound of claim 15 . A pharmaceutical composition for the treatment of bowel disease, (f) cystic fibrosis, or (g) an abdominal aortic aneurysm. 16. (a) rheumatoid arthritis, (b) asthma, (c) chronic obstructive pulmonary disease, (d) sepsis, produced by mixing the compound of claim 15 and a pharmaceutically acceptable carrier. A pharmaceutical composition for the treatment of (e) irritable bowel disease, (f) cystic fibrosis, or (g) an abdominal aortic aneurysm. (A) rheumatoid arthritis, (b) asthma, (c) chronic obstructive pulmonary disease, (d) sepsis, comprising mixing a compound of claim 15 and a pharmaceutically acceptable carrier. e) A method for producing a pharmaceutical composition for the treatment of irritable bowel disease, (f) cystic fibrosis, or (g) an abdominal aortic aneurysm. (A) rheumatoid arthritis, (b) asthma, (c) chronic obstructive pulmonary disease, (d) sepsis, (e) irritable bowel disease, (f) cystic fibrosis, or (g) abdominal aortic aneurysm Use of a compound according to claim 15 for the preparation of a medicament for treating them in a patient in need of treatment.